Dipeptidyl peptidase inhibitors

ABSTRACT

Compounds are provided for use with DPP-IV of the formula:  
                 
Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods and intermediates useful for making the compounds; and methods of using said compounds.

RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.11/080,992, filed Mar. 15, 2005, which claims the benefit of U.S.Provisional Application No. 60/553,571 filed Mar. 15, 2004 and U.S.Provisional Application No. 60/629,524 filed Nov. 18, 2004, all of whichare incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to compounds that may be used to inhibitdipeptidyl peptidases as well as compositions of matter and kitscomprising these compounds. The present invention also relates tomethods for inhibiting dipeptidyl peptidases as well as treatmentmethods using compounds according to the present invention.

DESCRIPTION OF RELATED ART

Dipeptidyl Peptidase IV (IUBMB Enzyme Nomenclature EC.3.4.14.5) is atype II membrane protein that has been referred to in the literature bya wide a variety of names including DPP4, DP4, DAP-IV, FAPβ, adenosinedeaminase complexing protein 2, adenosine deaminase binding protein(ADAbp), dipeptidyl aminopeptidase IV;Xaa-Pro-dipeptidyl-aminopeptidase; Gly-Pro naphthylamidase; postprolinedipeptidyl aminopeptidase IV; lymphocyte antigen CD26; glycoproteinGP110; dipeptidyl peptidase IV; glycylproline aminopeptidase;glycylproline aminopeptidase; X-prolyl dipeptidyl aminopeptidase; pep X;leukocyte antigen CD26; glycylprolyl dipeptidylaminopeptidase;dipeptidyl-peptide hydrolase; glycylprolyl aminopeptidase;dipeptidyl-aminopeptidase IV; DPP IV/CD26; amino acyl-prolyl dipeptidylaminopeptidase; T cell triggering molecule Tp103; X-PDAP. DipeptidylPeptidase IV is referred to herein as “DPP-IV.”

DPP-IV is a non-classical serine aminodipeptidase that removes Xaa-Prodipeptides from the amino terminus (N-terminus) of polypeptides andproteins. DPP-IV dependent slow release of dipeptides of the type X-Glyor X-Ser has also been reported for some naturally occurring peptides.

DPP-IV is constitutively expressed on epithelial and endothelial cellsof a variety of different tissues (intestine, liver, lung, kidney andplacenta), and is also found in body fluids. DPP-IV is also expressed oncirculating T-lymphocytes and has been shown to be synonymous with thecell-surface antigen, CD-26. DPP-IV has been implicated in a number ofdisease states, some of which are discussed below.

DPP-IV is responsible for the metabolic cleavage of certain endogenouspeptides (GLP-1 (7-36), glucagon) in vivo and has demonstratedproteolytic activity against a variety of other peptides (GHRH, NPY,GLP-2, VIP) in vitro.

GLP-1 (7-36) is a 29 amino-acid peptide derived by post-translationalprocessing of proglucagon in the small intestine. GLP-1 (7-36) hasmultiple actions in vivo including the stimulation of insulin secretion,inhibition of glucagon secretion, the promotion of satiety, and theslowing of gastric emptying. Based on its physiological profile, theactions of GLP-1 (7-36) are believed to be beneficial in the preventionand treatment of type II diabetes and potentially obesity. For example,exogenous administration of GLP-1 (7-36) (continuous infusion) indiabetic patients has been found to be efficacious in this patientpopulation. Unfortunately, GLP-1 (7-36) is degraded rapidly in vivo andhas been shown to have a short half-life in vivo (t_(1/2)=1.5 minutes).

Based on a study of genetically bred DPP-IV knock out mice and on invivo/in vitro studies with selective DPP-IV inhibitors, DPP-IV has beenshown to be the primary degrading enzyme of GLP-1 (7-36) in vivo. GLP-1(7-36) is degraded by DPP-IV efficiently to GLP-1 (9-36), which has beenspeculated to act as a physiological antagonist to GLP-1 (7-36).Inhibiting DPP-IV in vivo is therefore believed to be useful forpotentiating endogenous levels of GLP-1 (7-36) and attenuating theformation of its antagonist GLP-1 (9-36). Thus, DPP-IV inhibitors arebelieved to be useful agents for the prevention, delay of progression,and/or treatment of conditions mediated by DPP-IV, in particulardiabetes and more particularly, type 2 diabetes mellitus, diabeticdislipidemia, conditions of impaired glucose tolerance (IGT), conditionsof impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis,appetite regulation and obesity.

DPP-IV expression is increased in T-cells upon mitogenic or antigenicstimulation (Mattem, T., et al., Scand. J. Immunol., 1991, 33, 737). Ithas been reported that inhibitors of DPP-IV and antibodies to DPP-IVsuppress the proliferation of mitogen-stimulated and antigen-stimulatedT-cells in a dose-dependant manner (Schon, E., et al., Biol. Chem.,1991, 372, 305). Various other functions of T-lymphocytes such ascytokine production, IL-2 mediated cell proliferation and B-cell helperactivity have been shown to be dependent on DPP-IV activity (Schon, E.,et al., Scand. J. Immunol, 1989, 29, 127). DPP-IV inhibitors, based onboroProline, (Flentke, G. R., et al., Proc. Nat. Acad. Sci. USA, 1991,88, 1556) although unstable, were effective at inhibitingantigen-induced lymphocyte proliferation and IL-2 production in murineCD4+ T-helper cells. Such boronic acid inhibitors have been shown tohave an effect in vivo in mice causing suppression of antibodyproduction induced by immune challenge (Kubota, T. et al., Clin. Exp.Immun., 1992, 89, 192). The role of DPP-IV in regulating T lymphocyteactivation may also be attributed, in part, to its cell-surfaceassociation with the transmembrane phosphatase, CD45. DPP-IV inhibitorsor non-active site ligands may possibly disrupt the CD45-DPP-IVassociation. CD45 is known to be an integral component of the T-cellsignaling apparatus. It has been reported that DPP-IV is essential forthe penetration and infectivity of HIV-1 and HIV-2 viruses in CD4+T-cells (Wakselman, M., Nguyen, C., Mazaleyrat, J.-P., Callebaut, C.,Krust, B., Hovanessian, A. G., Inhibition of HIV-1 infection of CD 26+but not CD 26-cells by a potent cyclopeptidic inhibitor of the DPP-IVactivity of CD 26. Abstract P.44 of the 24.sup.th European PeptideSymposium 1996). Additionally, DPP-IV has been shown to associate withthe enzyme adenosine deaminase (ADA) on the surface of T-cells (Kameoka,J., et al., Science, 193, 26 466). ADA deficiency causes severe combinedimmunodeficiency disease (SCID) in humans. This ADA-CD26 interaction mayprovide clues to the pathophysiology of SCID. It follows that inhibitorsof DPP-IV may be useful immunosuppressants (or cytokine releasesuppressant drugs) for the treatment of among other things: organtransplant rejection; autoimmune diseases such as inflammatory boweldisease, multiple sclerosis and rheumatoid arthritis; and the treatmentof AIDS.

It has been shown that lung endothelial cell DPP-IV is an adhesionmolecule for lung-metastatic rat breast and prostate carcinoma cells(Johnson, R. C., et al., J. Cell. Biol., 1993, 121, 1423). DPP-IV isknown to bind to fibronectin and some metastatic tumor cells are knownto carry large amounts of fibronectin on their surface. Potent DPP-IVinhibitors may be useful as drugs to prevent metastases of, for example,breast and prostrate tumors to the lungs.

High levels of DPP-IV expression have also been found in human skinfibroblast cells from patients with psoriasis, rheumatoid arthritis (RA)and lichen planus (Raynaud, F., et al., J. Cell. Physiol., 1992, 151,378). Therefore, DPP-IV inhibitors may be useful as agents to treatdermatological diseases such as psoriasis and lichen planus.

High DPP-IV activity has been found in tissue homogenates from patientswith benign prostate hypertrophy and in prostatosomes. These areprostate derived organelles important for the enhancement of spermforward motility (Vanhoof, G., et al., Eur. J. Clin. Chem. Clin.Biochem., 1992, 30, 333). DPP-IV inhibitors may also act to suppresssperm motility and therefore act as a male contraceptive agent.Conversely, DPP-IV inhibitors have been implicated as novel fortreatment of infertility, and particularly human female infertility dueto Polycystic ovary syndrome (PCOS, Stein-Leventhal syndrome) which is acondition characterized by thickening of the ovarian capsule andformation of multiple follicular cysts. It results in infertility andamenorrhea.

DPP-IV is thought to play a role in the cleavage of various cytokines(stimulating hematopoietic cells), growth factors and neuropeptides.

Stimulated hematopoietic cells are useful for the treatment of disordersthat are characterized by a reduced number of hematopoietic cells ortheir precursors in vivo. Such conditions occur frequently in patientswho are immunosuppressed, for example, as a consequence of chemotherapyand/or radiation therapy for cancer. It was discovered that inhibitorsof dipeptidyl peptidase type IV are useful for stimulating the growthand differentiation of hematopoietic cells in the absence of exogenouslyadded cytokines or other growth factors or stromal cells. This discoverycontradicts the dogma in the field of hematopoietic cell stimulation,which provides that the addition of cytokines or cells that producecytokines (stromal cells) is an essential element for maintaining andstimulating the growth and differentiation of hematopoietic cells inculture. (See, e.g., PCT Intl. Application No. PCT/US93/017173 publishedas WO 94/03055).

DPP-IV in human plasma has been shown to cleave N-terminal Tyr-Ala fromgrowth hormone-releasing factor and cause inactivation of this hormone.Therefore, inhibitors of DPP-IV may be useful in the treatment of shortstature due to growth hormone deficiency (Dwarfism) and for promotingGH-dependent tissue growth or re-growth.

DPP-IV can also cleave neuropeptides and has been shown to modulate theactivity of neuroactive peptides substance P, neuropeptide Y and CLIP(Mentlein, R., Dahms, P., Grandt, D., Kruger, R., Proteolytic processingof neuropeptide Y and peptide YY by dipeptidyl peptidase IV, Regul.Pept., 49, 133, 1993; Wetzel, W., Wagner, T., Vogel, D., Demuth, H.-U.,Balschun, D., Effects of the CLIP fragment ACTH 20-24 on the duration ofREM sleep episodes, Neuropeptides, 31, 41, 1997). Thus DPP-IV inhibitorsmay also be useful agents for the regulation or normalization ofneurological disorders.

Several compounds have been shown to inhibit DPP-IV. Nonetheless, a needstill exists for new DPP-IV inhibitors that have advantageous potency,stability, selectivity, toxicity and/or pharmacodynamics properties. Inthis regard, a novel class of DPP-IV inhibitors are provided herein.

SUMMARY OF THE INVENTION

The present invention relates to compounds that have activity forinhibiting DPP-IV. It is noted that these compounds may also haveactivity for inhibiting other S9 proteases and thus may be used againstthese other S9 proteases as well as DPP-IV. The present invention alsoprovides compositions, articles of manufacture and kits comprising thesecompounds.

In one embodiment, a pharmaceutical composition is provided thatcomprises a DPP-IV inhibitor according to the present invention as anactive ingredient. Pharmaceutical compositions according to theinvention may optionally comprise 0.001%-100% of one or more DPP-IVinhibitors of this invention. These pharmaceutical compositions may beadministered or coadministered by a wide variety of routes, includingfor example, orally, parenterally, intraperitoneally, intravenously,intraarterially, transdermally, sublingually, intramuscularly, rectally,transbuccally, intranasally, liposomally, via inhalation, vaginally,intraoccularly, via local delivery (for example by catheter or stent),subcutaneously, intraadiposally, intraarticularly, or intrathecally. Thecompositions may also be administered or coadministered in slow releasedosage forms.

The invention is also directed to kits and other articles of manufacturefor treating disease states associated with DPP-IV.

In one embodiment, a kit is provided that comprises a compositioncomprising at least one DPP-IV inhibitor of the present invention incombination with instructions. The instructions may indicate the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also comprise packagingmaterials. The packaging material may comprise a container for housingthe composition. The kit may also optionally comprise additionalcomponents, such as syringes for administration of the composition. Thekit may comprise the composition in single or multiple dose forms.

In another embodiment, an article of manufacture is provided thatcomprises a composition comprising at least one DPP-IV inhibitor of thepresent invention in combination with packaging materials. The packagingmaterial may comprise a container for housing the composition. Thecontainer may optionally comprise a label indicating the disease statefor which the composition is to be administered, storage information,dosing information and/or instructions regarding how to administer thecomposition. The kit may also optionally comprise additional components,such as syringes for administration of the composition. The kit maycomprise the composition in single or multiple dose forms.

Also provided are methods for preparing compounds, compositions and kitsaccording to the present invention. For example, several syntheticschemes are provided herein for synthesizing compounds according to thepresent invention.

Also provided are methods for using compounds, compositions, kits andarticles of manufacture according to the present invention.

In one embodiment, the compounds, compositions, kits and articles ofmanufacture are used to inhibit DPP-IV.

In another embodiment, the compounds, compositions, kits and articles ofmanufacture are used to treat a disease state for which DPP-IV possessesactivity that contributes to the pathology and/or symptomology of thedisease state.

In another embodiment, a compound is administered to a subject whereinDPP-IV activity within the subject is altered, preferably reduced.

In another embodiment, a prodrug of a compound is administered to asubject that is converted to the compound in vivo where it inhibitsDPP-IV.

In another embodiment, a method of inhibiting DPP-IV is provided thatcomprises contacting DPP-IV with a compound according to the presentinvention.

In another embodiment, a method of inhibiting DPP-IV is provided thatcomprises causing a compound according to the present invention to bepresent in a subject in order to inhibit DPP-IV in vivo.

In another embodiment, a method of inhibiting DPP-IV is provided thatcomprises administering a first compound to a subject that is convertedin vivo to a second compound wherein the second compound inhibits DPP-IVin vivo. It is noted that the compounds of the present invention may bethe first or second compounds.

In another embodiment, a therapeutic method is provided that comprisesadministering a compound according to the present invention.

In another embodiment, a method of inhibiting cell proliferation isprovided that comprises contacting a cell with an effective amount of acompound according to the present invention.

In another embodiment, a method of inhibiting cell proliferation in apatient is provided that comprises administering to the patient atherapeutically effective amount of a compound according to the presentinvention.

In another embodiment, a method of treating a condition in a patientwhich is known to be mediated by DPP-IV, or which is known to be treatedby DPP-IV inhibitors, comprising administering to the patient atherapeutically effective amount of a compound according to the presentinvention.

In another embodiment, a method is provided for using a compoundaccording to the present invention in order to manufacture a medicamentfor use in the treatment of disease state which is known to be mediatedby DPP-IV, or which is known to be treated by DPP-IV inhibitors.

In another embodiment, a method is provided for treating a disease statefor which DPP-IV possesses activity that contributes to the pathologyand/or symptomology of the disease state, the method comprising: causinga compound according to the present invention to be present in a subjectin a therapeutically effective amount for the disease state.

In another embodiment, a method is provided for treating a disease statefor which DPP-IV possesses activity that contributes to the pathologyand/or symptomology of the disease state, the method comprising:administering a first compound to a subject that is converted in vivo toa second compound such that the second compound is present in thesubject in a therapeutically effective amount for the disease state. Itis noted that the compounds of the present invention may be the first orsecond compounds.

In another embodiment, a method is provided for treating a disease statefor which DPP-IV possesses activity that contributes to the pathologyand/or symptomology of the disease state, the method comprising:administering a compound according to the present invention to a subjectsuch that the compound is present in the subject in a therapeuticallyeffective amount for the disease state.

In another embodiment, a method is provided for treating a cellproliferative disease state comprising treating cells with a compoundaccording to the present invention in combination with ananti-proliferative agent, wherein the cells are treated with thecompound according to the present invention before, at the same time,and/or after the cells are treated with the anti-proliferative agent,referred to herein as combination therapy. It is noted that treatment ofone agent before another is referred to herein as sequential therapy,even if the agents are also administered together. It is noted thatcombination therapy is intended to cover when agents are administeredbefore or after each other (sequential therapy) as well as when theagents are administered at the same time.

Examples of diseases that may be treated by administration of compoundsand compositions according to the present invention include, but are notlimited to conditions mediated by DPP-IV, in particular diabetes, moreparticular type 2 diabetes mellitus, diabetic dislipidemia, conditionsof impaired glucose tolerance (IGT), conditions of impaired fastingplasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation,obesity, immunosuppressants or cytokine release regulation, autoimmunediseases such as inflammatory bowel disease, multiple sclerosis andrheumatoid arthritis, AIDS, cancers (prevention of metastases, forexample, breast and prostrate tumors to the lungs), dermatologicaldiseases such as psoriasis and lichen planus, treatment of femaleinfertility, osteoporosis, male contraception and neurologicaldisorders.

It is noted in regard to all of the above embodiments that the presentinvention is intended to encompass all pharmaceutically acceptableionized forms (e.g., salts) and solvates (e.g., hydrates) of thecompounds, regardless of whether such ionized forms and solvates arespecified since it is well known in the art to administer pharmaceuticalagents in an ionized or solvated form. It is also noted that unless aparticular stereochemistry is specified, recitation of a compound isintended to encompass all possible stereoisomers (e.g., enantiomers ordiastereomers depending on the number of chiral centers), independent ofwhether the compound is present as an individual isomer or a mixture ofisomers. Further, unless otherwise specified, recitation of a compoundis intended to encompass all possible resonance forms and tautomers.With regard to the claims, the language “compound comprising theformula” is intended to encompass the compound and all pharmaceuticallyacceptable ionized forms and solvates, all possible stereoisomers, andall possible resonance forms and tautomers unless otherwise specificallyspecified in the particular claim.

It is further noted that prodrugs may also be administered which arealtered in vivo and become a compound according to the presentinvention. The various methods of using the compounds of the presentinvention are intended, regardless of whether prodrug delivery isspecified, to encompass the administration of a prodrug that isconverted in vivo to a compound according to the present invention. Itis also noted that certain compounds of the present invention may bealtered in vivo prior to inhibiting DPP-IV and thus may themselves beprodrugs for another compound. Such prodrugs of another compound may ormay not themselves independently have DPP-IV inhibitory activity.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 illustrates a ribbon diagram overview of the structure of DPP-IV,highlighting the secondary structural elements of the protein.

DEFINITIONS

Unless otherwise stated, the following terms used in the specificationand claims shall have the following meanings for the purposes of thisapplication.

“Alicyclic” means a moiety comprising a non-aromatic ring structure.Alicyclic moieties may be saturated or partially unsaturated with one,two or more double or triple bonds. Alicyclic moieties may alsooptionally comprise heteroatoms such as nitrogen, oxygen and sulfur. Thenitrogen atoms can be optionally quaternerized or oxidized and thesulfur atoms can be optionally oxidized. Examples of alicyclic moietiesinclude, but are not limited to moieties with C3-C8 rings such ascyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene,cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene,cycloheptadiene, cyclooctane, cyclooctene, and cyclooctadiene.

“Aliphatic” means a moiety characterized by a straight or branched chainarrangement of constituent carbon atoms and may be saturated orpartially unsaturated with one, two or more double or triple bonds.

“Alkenyl” represented by itself means a straight or branched,unsaturated, aliphatic radical having a chain of carbon atoms having atleast one double bond between adjacent carbon atoms. C_(X) alkenyl andC_(X-Y) alkenyl are typically used where X and Y indicate the number ofcarbon atoms in the chain. For example, C₂₋₆ alkenyl includes alkenylsthat have a chain of between 2 and 6 carbons.

“Alkoxy” means an oxygen moiety having a further alkyl substituent. Thealkoxy groups of the present invention can be optionally substituted.

“Alkyl” represented by itself means a straight or branched, saturated orunsaturated, aliphatic radical having a chain of carbon atoms,optionally with oxygen (See “oxaalkyl”) or nitrogen atoms (See“aminoalkyl”) between the carbon atoms. C_(X) alkyl and C_(X-Y) alkylare typically used where X and Y indicate the number of carbon atoms inthe chain. For example, C₁₋₆ alkyl includes alkyls that have a chain ofbetween 1 and 6 carbons (e.g., methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, isopropenyl,1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl,2-propynyl, and the like). Alkyl represented along with another radical(e.g., as in arylalkyl, heteroarylalkyl) means a straight or branched,saturated or unsaturated aliphatic divalent radical having the number ofatoms indicated or when no atoms are indicated means a bond (e.g.,(C₆₋₁₀)aryl(C₁₋₃)alkyl includes, benzyl, phenethyl, 1-phenylethyl,3-phenylpropyl, 2-thienylmethyl, 2-pyridinylmethyl and the like).

“Alkylene”, unless indicated otherwise, means a straight or branched,saturated or unsaturated, aliphatic, divalent radical. C_(X) alkyleneand C_(X-Y) alkylene are typically used where X and Y indicate thenumber of carbon atoms in the chain. For example, C₁₋₆ alkylene includesmethylene (—CH₂—), ethylene (—CH₂CH₂—), trimethylene (—CH₂CH₂CH₂—),tetramethylene (—CH₂CH₂CH₂CH₂—) 2-butenylene (—CH₂CH═CHCH₂—),2-methyltetramethylene (—CH₂CH(CH₃)CH₂CH₂—), pentamethylene(—CH₂CH₂CH₂CH₂CH₂—) and the like).

“Alkylidene” means a straight or branched saturated or unsaturated,aliphatic radical connected to the parent molecule by a double bond.C_(X) alkylidene and C_(X-Y) alkylidene are typically used where X and Yindicate the number of carbon atoms in the chain. For example, C₁₋₆alkylidene includes methylene (═CH₂), ethylidene (═CHCH₃),isopropylidene (═C(CH₃)₂), propylidene (═CHCH₂CH₃), allylidene(═CH—CH═CH₂), and the like).

“Alkynyl” represented by itself means a straight or branched,unsaturated, aliphatic radical having a chain of carbon atoms having atleast one triple bond between adjacent carbon atoms. C_(X) alkynyl andC_(X-Y) alkynyl are typically used where X and Y indicate the number ofcarbon atoms in the chain. For example, C₂₋₆ alkynyl includes alkynylsthat have a chain of between 2 and 6 carbons.

“Amino” means a nitrogen moiety having two further substituents where ahydrogen or carbon atom is attached to the nitrogen. For example,representative amino groups include —NH₂, —NHCH₃, —N(CH₃)₂,—NHC₁₋₃-alkyl, —N(C₁₋₃-alkyl)₂ and the like. Unless indicated otherwise,the compounds of the invention containing amino moieties may includeprotected derivatives thereof. Suitable protecting groups for aminomoieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and thelike.

“Aminoalkyl” means an alkyl, as defined above, except where one or moresubstituted or unsubstituted nitrogen atoms (—N—) are positioned betweencarbon atoms of the alkyl. For example, an (C₂₋₆) aminoalkyl refers to achain comprising between 2 and 6 carbons and one or more nitrogen atomspositioned between the carbon atoms.

“Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits,cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals(e.g., birds, and the like).

“Aromatic” means a moiety wherein the constituent atoms make up anunsaturated ring system, all atoms in the ring system are sp² hybridizedand the total number of pi electrons is equal to 4n+2. An aromatic ringmay be such that the ring atoms are only carbon atoms or may includecarbon and non-carbon atoms (see Heteroaryl).

“Aryl” means a monocyclic or polycyclic ring assembly wherein each ringis aromatic or when fused with one or more rings forms an aromatic ringassembly. If one or more ring atoms is not carbon (e.g., N, S), the arylis a heteroaryl. C_(X) aryl and C_(X-Y) aryl are typically used where Xand Y indicate the number of atoms in the ring.

“Bicycloalkyl” means a saturated or partially unsaturated fused bicyclicor bridged polycyclic ring assembly.

“Bicycloaryl” means a bicyclic ring assembly wherein the rings arelinked by a single bond or fused and at least one of the ringscomprising the assembly is aromatic. C_(X) bicycloaryl and C_(X-Y)bicycloaryl are typically used where X and Y indicate the number ofcarbon atoms in the bicyclic ring assembly and directly attached to thering.

“Bridging ring” as used herein refers to a ring that is bonded toanother ring to form a compound having a bicyclic structure where tworing atoms that are common to both rings are not directly bound to eachother. Non-exclusive examples of common compounds having a bridging ringinclude borneol, norbornane, 7-oxabicyclo[2.2.1]heptane, and the like.One or both rings of the bicyclic system may also comprise heteroatoms.

“Carbamoyl” means the radical —OC(O)NR_(a)R_(b) where R_(a) and R_(b)are each independently two further substituents where a hydrogen orcarbon atom is attached to the nitrogen.

“Carbocycle” means a ring consisting of carbon atoms.

“Carbocyclic ketone derivative” means a carbocyclic derivative whereinthe ring contains a —CO— moiety.

“Carbonyl” means the radical —CO—. It is noted that the carbonyl radicalmay be further substituted with a variety of substituents to formdifferent carbonyl groups including acids, acid halides, aldehydes,amides, esters, and ketones.

“Carboxy” means the radical —CO₂—. It is noted that compounds of theinvention containing carboxy moieties may include protected derivativesthereof, i.e., where the oxygen is substituted with a protecting group.Suitable protecting groups for carboxy moieties include benzyl,tert-butyl, and the like.

“Cyano” means the radical —CN.

“Cycloalkyl” means a non-aromatic, saturated or partially unsaturated,monocyclic, fused bicyclic or bridged polycyclic ring assembly. C_(X)cycloalkyl and C_(X-Y) cycloalkyl are typically used where X and Yindicate the number of carbon atoms in the ring assembly. For example,C₃₋₁₀ cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl, bicyclo[2.2.2]octyl,adamantan-1-yl, decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl,thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl, and the like.

“Cycloalkylene” means a divalent saturated or partially unsaturated,monocyclic or polycyclic ring assembly. C_(X) cycloalkylene and C_(X-Y)cycloalkylene are typically used where X and Y indicate the number ofcarbon atoms in the ring assembly.

“Disease” specifically includes any unhealthy condition of an animal orpart thereof and includes an unhealthy condition that may be caused by,or incident to, medical or veterinary therapy applied to that animal,i.e., the “side effects” of such therapy.

“Fused ring” as used herein refers to a ring that is bonded to anotherring to form a compound having a bicyclic structure where the ring atomsthat are common to both rings are directly bound to each other.Non-exclusive examples of common fused rings include decalin,naphthalene, anthracene, phenanthrene, indole, furan, benzofuran,quinoline, and the like. Compounds having fused ring systems may besaturated, partially saturated, carbocyclics, heterocyclics, aromatics,heteroaromatics, and the like.

“Halo” means fluoro, chloro, bromo or iodo.

“Halo-substituted alkyl”, as an isolated group or part of a largergroup, means “alkyl” substituted by one or more “halo” atoms, as suchterms are defined in this application. Halo-substituted alkyl includeshaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g.halo-substituted (C₁₋₃)alkyl includes chloromethyl, dichloromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl,2,2,2-trifluoro-1,1-dichloroethyl, and the like).

“Heteroatom” refers to an atom that is not a carbon atom. Particularexamples of heteroatoms include, but are not limited to nitrogen,oxygen, and sulfur.

“Heteroatom moiety” includes a moiety where the atom by which the moietyis attached is not a carbon. Examples of heteroatom moieties include—N═, —NR_(c)—, —N⁺(O⁻)═, —O—, —S— or —S(O)₂—, wherein R_(c) is furthersubstituent.

“Heterobicycloalkyl” means bicycloalkyl, as defined in this application,provided that one or more of the atoms within the ring is a heteroatom.For example hetero(C₉₋₁₂)bicycloalkyl as used in this applicationincludes, but is not limited to, 3-aza-bicyclo[4.1.0]hept-3-yl,2-aza-bicyclo[3.1.0]hex-2-yl, 3-aza-bicyclo[3.1.0]hex-3-yl, and thelike.

“Heterocycloalkylene” means cycloalkylene, as defined in thisapplication, provided that one or more of the ring member carbon atomsis replaced by a heteroatom.

“Heteroaryl” means a cyclic aromatic group having five or six ringatoms, wherein at least one ring atom is a heteroatom and the remainingring atoms are carbon. The nitrogen atoms can be optionallyquaternerized and the sulfur atoms can be optionally oxidized.Heteroaryl groups of this invention include, but are not limited to,those derived from furan, imidazole, isothiazole, isoxazole, oxadiazole,oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine,pyrimidine, pyrroline, thiazole, 1,3,4-thiadiazole, triazole andtetrazole. “Heteroaryl” also includes, but is not limited to, bicyclicor tricyclic rings, wherein the heteroaryl ring is fused to one or tworings independently selected from the group consisting of an aryl ring,a cycloalkyl ring, a cycloalkenyl ring, and another monocyclicheteroaryl or heterocycloalkyl ring. These bicyclic or tricyclicheteroaryls include, but are not limited to, those derived frombenzo[b]furan, benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine,quinazoline, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine,thieno[2,3-b]pyridine, indolizine, imidazo[1,2a]pyridine, quinoline,isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolizine,indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole,benzothiazole, imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine,imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine,imidazo[1,5-a]pyrimidine, imidazo[1,5-c]pyrimidine,pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine,pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine,pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-b]pyrazine,pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine,pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrimidine,pyrrolo[1,2-a]pyrazine, triazo[1,5-a]pyridine, pteridine, purine,carbazole, acridine, phenazine, phenothiazene, phenoxazine,1,2-dihydropyrrolo[3,2,1-hi]indole, indolizine, pyrido[1,2-a]indole and2(1H)-pyridinone. The bicyclic or tricyclic heteroaryl rings can beattached to the parent molecule through either the heteroaryl groupitself or the aryl, cycloalkyl, cycloalkenyl or heterocycloalkyl groupto which it is fused. The heteroaryl groups of this invention can besubstituted or unsubstituted.

“Heterobicycloaryl” means bicycloaryl, as defined in this application,provided that one or more of the atoms within the ring is a heteroatom.For example, hetero(C₄₋₁₀)bicycloaryl as used in this applicationincludes, but is not limited to, 2-amino-4-oxo-3,4-dihydropteridin-6-yl,tetrahydroisoquinolinyl, and the like.

“Heterocycloalkyl” means cycloalkyl, as defined in this application,provided that one or more of the atoms forming the ring is a heteroatomselected, independently from N, O, or S. Non-exclusive examples ofheterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl,pyrrolidinyl, perhydropyrrolizinyl, 1,4-diazaperhydroepinyl,1,3-dioxanyl, 1,4-dioxanyl and the like.

“Hydroxy” means the radical —OH.

“Iminoketone derivative” means a derivative comprising the moiety—C(NR)—, wherein R comprises a hydrogen or carbon atom attached to thenitrogen.

“Isomers” mean any compound having an identical molecular formulae butdiffering in the nature or sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers.”Stereoisomers that are not mirror images of one another are termed“diastereomers” and stereoisomers that are nonsuperimposable mirrorimages are termed “enantiomers” or sometimes “optical isomers.” A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter.” A compound with one chiral center has two enantiomeric forms ofopposite chirality. A mixture of the two enantiomeric forms is termed a“racemic mixture.” A compound that has more than one chiral center has2^(n-1) enantiomeric pairs, where n is the number of chiral centers.Compounds with more than one chiral center may exist as ether anindividual diastereomer or as a mixture of diastereomers, termed a“diastereomeric mixture.” When one chiral center is present astereoisomer may be characterized by the absolute configuration of thatchiral center. Absolute configuration refers to the arrangement in spaceof the substituents attached to the chiral center. Enantiomers arecharacterized by the absolute configuration of their chiral centers anddescribed by the R- and S-sequencing rules of Cahn, Ingold and Prelog.Conventions for stereochemical nomenclature, methods for thedetermination of stereochemistry and the separation of stereoisomers arewell known in the art (e.g., see “Advanced Organic Chemistry”, 4thedition, March, Jerry, John Wiley & Sons, New York, 1992).

“Nitro” means the radical —NO₂.

“Oxaalkyl” means an alkyl, as defined above, except where one or moreoxygen atoms (—O—) are positioned between carbon atoms of the alkyl. Forexample, an (C₂₋₆)oxaalkyl refers to a chain comprising between 2 and 6carbons and one or more oxygen atoms positioned between the carbonatoms.

“Oxoalkyl” means an alkyl, further substituted with a carbonyl group.The carbonyl group may be an aldehyde, ketone, ester, amide, acid oracid chloride.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means salts of inhibitors of thepresent invention which are pharmaceutically acceptable, as definedabove, and which possess the desired pharmacological activity. Suchsalts include acid addition salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or with organic acids such as aceticacid, propionic acid, hexanoic acid, heptanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartatic acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, p-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonicacid, 4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid),3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike.

“Prodrug” means a compound that is convertible in vivo metabolicallyinto an inhibitor according to the present invention. The prodrug itselfmay or may not also have DPP-IV inhibitory activity. For example, aninhibitor comprising a hydroxy group may be administered as an esterthat is converted by hydrolysis in vivo to the hydroxy compound.Suitable esters that may be converted in vivo into hydroxy compoundsinclude acetates, citrates, lactates, tartrates, malonates, oxalates,salicylates, propionates, succinates, fumarates, maleates,methylene-bis-b-hydroxynaphthoates, gentisates, isethionates,di-p-toluoyltartrates, methanesulfonates, ethanesulfonates,benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates,esters of amino acids, and the like. Similarly, an inhibitor comprisingan amine group may be administered as an amide that is converted byhydrolysis in vivo to the amine compound.

“Protected derivatives” means derivatives of inhibitors in which areactive site or sites are blocked with protecting groups. Protectedderivatives are useful in the preparation of inhibitors or in themselvesmay be active as inhibitors. A comprehensive list of suitable protectinggroups can be found in T. W. Greene, Protecting Groups in OrganicSynthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

“Substituted or unsubstituted” means that a given moiety may consist ofonly hydrogen substituents through available valencies (unsubstituted)or may further comprise one or more non-hydrogen substituents throughavailable valencies (substituted) that are not otherwise specified bythe name of the given moiety. For example, isopropyl is an example of anethylene moiety that is substituted by —CH₃. In general, a non-hydrogensubstituent may be any substituent that may be bound to an atom of thegiven moiety that is specified to be substituted. Examples ofsubstituents include, but are not limited to, aldehyde, alicyclic,aliphatic, alkyl, alkylene, alkylidene, amide, amino, aminoalkyl,aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl,carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester, halo,heterobicycloalkyl, heterocycloalkylene, heteroaryl, heterobicycloaryl,heterocycloalkyl, oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl,and oxoalkyl moieties, each of which may optionally also be substitutedor unsubstituted.

“Sulfinyl” means the radical —SO—. It is noted that the sulfinyl radicalmay be further substituted with a variety of substituents to formdifferent sulfinyl groups including sulfinic acids, sulfinamides,sulfinyl esters, and sulfoxides.

“Sulfonyl” means the radical —SO₂—. It is noted that the sulfonylradical may be further substituted with a variety of substituents toform different sulfonyl groups including sulfonic acids, sulfonamides,sulfonate esters, and sulfones.

“Therapeutically effective amount” means that amount which, whenadministered to an animal for treating a disease, is sufficient toeffect such treatment for the disease.

“Thiocarbonyl” means the radical —CS—. It is noted that the thiocarbonylradical may be further substituted with a variety of substituents toform different thiocarbonyl groups including thioacids, thioamides,thioesters, and thioketones.

“Treatment” or “treating” means any administration of a compound of thepresent invention and includes:

(1) preventing the disease from occurring in an animal which may bepredisposed to the disease but does not yet experience or display thepathology or symptomatology of the disease,

(2) inhibiting the disease in an animal that is experiencing ordisplaying the pathology or symptomatology of the diseased (i.e.,arresting further development of the pathology and/or symptomatology),or

(3) ameliorating the disease in an animal that is experiencing ordisplaying the pathology or symptomatology of the disease (i.e.,reversing the pathology and/or symptomatology).

It is noted in regard to all of the definitions provided herein that thedefinitions should be interpreted as being open ended in the sense thatfurther substituents beyond those specified may be included. Hence, a C₁alkyl indicates that there is one carbon atom but does not indicate whatare the substituents on the carbon atom. Hence, a C₁ alkyl comprisesmethyl (i.e., —CH₃) as well as —R_(a)R_(b)R_(c), where R_(a), R_(b), andR_(c) may each independently be hydrogen or any other substituent wherethe atom attached to the carbon is a heteroatom or cyano. Hence, CF₃,CH₂OH and CH₂CN, for example, are all C₁ alkyls.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds, compositions, kits andarticles of manufacture that may be used to inhibit dipeptidylpeptidases IV (referred to herein as DPP-IV).

DPP-IV (EC.3.4.14.5 also known as DPP4, DP4, DAP-IV, adenosine deaminasecomplexing protein 2, adenosine deaminase binding protein (ADAbp) orCD26) is a 766 residue, 240 kDa protein that is a highly specificmembrane bound non-classical serine aminodipeptidase. DPP-IV has aserine type mechanism of protease activity, cleaving off dipeptides fromthe amino-terminus of peptides with proline or alanine at thepenultimate position. In addition the slow release of dipeptides of thetype X-Gly or X-Ser is reported for some naturally occurring peptides.DPP-IV is constitutively expressed on epithelial and endothelial cellsof a variety of different tissues (intestine, liver, lung, kidney andplacenta), and is also found in body fluids. DPP-IV is also expressed oncirculating T-lymphocytes and has been shown to be synonymous with thecell-surface antigen, CD-26. The wild-type form of full length DPP-IV isdescribed in GenBank Accession Number NM_(—)001935 (“Dipeptidylpeptidase IV (CD 26) gene expression in enterocyte-like colon cancercell lines HT-29 and Caco-2. Cloning of the complete human codingsequence and changes of dipeptidyl peptidase IV mRNA levels during celldifferentiation”, Darmoul, D., Lacasa, M., Baricault, L., Marguet, D.,Sapin, C., Trotot, P., Barbat, A. and Trugnan, G., J. Biol. Chem., 267(7), 4824-4833, 1992).

DPP-IV is a member of the S9 family of serine proteases, moreparticularly the S9B family. Other members of the S9 family include, butare not limited to:

-   -   Subfamily S9A: Dipeptidyl-peptidase; Oligopeptidase B (EC        3.4.21.83); Oligopeptidase B; Prolyl oligopeptidase (EC        3.4.21.26);    -   Subfamily S9B: Dipeptidyl aminopeptidase A; Dipeptidyl        aminopeptidase B Dipeptidyl-peptidase IV (EC 3.4.14.5);        Dipeptidyl-peptidase V Fibroblast activation protein alpha        subunit; Seprase    -   Subfamily S9C: Acylaminoacyl-peptidase (EC 3.4.19.1)

It is noted that the compounds of the present invention may also possessinhibitory activity for other S9 family members and thus may be used toaddress disease states associated with these other family members.

1. Crystal Structure of DPP-IV

Syrrx, Inc. (San Diego, Calif.) recently solved the crystal structure ofDPP-IV. Knowledge of the crystal structure was used to guide the designof the DPP-IV inhibitors provided herein.

FIG. 1 illustrates a ribbon diagram overview of the structure of DPP-IV,highlighting secondary structural elements of the protein. DPP-IV is acylindrical shaped molecule with an approximate height of 70 Å and adiameter of 60 Å. The catalytic triad of DPP-IV (Ser642, Asp720 andHis752) is illustrated in the center of the figure by a “ball and stick”representation. This triad of amino acids is located in the peptidasedomain or catalytic domain of DPP-IV. The catalytic domain is covalentlylinked to the β-propeller domain. The catalytic domain of DPP-IVincludes residues 1-67 and 511-778. The catalytic domain of DPP-IVadopts a characteristic α/β hydrolase fold. The core of this domaincontains an 8-stranded β-sheet with all strands being parallel exceptone. The α-sheet is significantly twisted and is flanked by threeα-helices on one side and five α-helices on the other. The topology ofthe β-strands is 1, 2, −1x, 2x and (1x) (J. S. Richardson: The anatomyand taxonomy of protein structure; (1981) Adv. Protein Chem. 269,15076-15084.). A number of residues were identified that contribute tothe shape and charge characteristics of the active site. Knowledge ofthese residues has been an important contribution to the design ofDPP-IV inhibitors of the present invention.

2. DPP-IV Inhibitors

In one embodiment, DPP-IV inhibitors of the present invention includecompounds comprising:

wherein

M is N or CR₄;

Q¹ and Q² are each independently selected from the group consisting ofCO, CS, SO, SO₂, and C═NR₉;

R₂ is hydrogen or selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,hetero(C₄₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted;

R₃ is selected from the group consisting of perhalo(C₁₋₁₀)alkyl, amino,(C₁₋₁₀)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,aryl, heteroaryl, carbonyl (C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl,sulfonyl (C₁₋₃)alkyl, sulfinyl (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted, and asubstituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;

R₄ is hydrogen or is selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, amino, cyano, thio, (C₁₋₁₀)alkyl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy,carbonyl group, imino group, sulfonyl group and sulfinyl group, eachsubstituted or unsubstituted;

R₉ is hydrogen or is selected from the group consisting of alkyl,cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl,and heterobicycloaryl, each substituted or unsubstituted;

L is a linker providing 1, 2 or 3 atom separation between X and the ringto which L is attached, wherein the atoms of the linker providing theseparation are selected from the group consisting of carbon, oxygen,nitrogen, and sulfur; and

X is selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl,carbonyl (C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl,sulfinyl (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl,hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonylgroup, cyano, imino group, sulfonyl group and sulfinyl group, eachsubstituted or unsubstituted.

In another embodiment, DPP-IV inhibitors of the present inventioninclude compounds comprising:

wherein

M is N or CR₄;

R₂ is hydrogen or selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,hetero(C₄₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted;

R₃ is selected from the group consisting of perhalo(C₁₋₁₀)alkyl, amino,(C₁₋₁₀)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,aryl, heteroaryl, carbonyl (C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl,sulfonyl (C₁₋₃)alkyl, sulfinyl (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted, and asubstituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;

R₄ is hydrogen or is selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, amino, cyano, thio, (C₁₋₁₀)alkyl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy,carbonyl group, imino group, sulfonyl group and sulfinyl group, eachsubstituted or unsubstituted;

L is a linker providing 1, 2 or 3 atom separation between X and the ringto which L is attached, wherein the atoms of the linker providing theseparation are selected from the group consisting of carbon, oxygen,nitrogen, and sulfur; and

X is selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl,carbonyl (C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl,sulfinyl (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl,hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonylgroup, cyano, imino group, sulfonyl group and sulfinyl group, eachsubstituted or unsubstituted.

Substituent L:

In one variation of the above embodiments, DPP-IV inhibitors of thepresent invention comprise compounds wherein the 1, 2 or 3 atoms of Lproviding the separation consist of carbon atoms. In another variation,the 1, 2 or 3 atoms of L providing the separation are selected from thegroup of linkers consisting of at least one oxygen or at least onenitrogen atom. In yet another variation, L separates X from the ringatom by one atom.

In one particular variation of the above embodiments, L is selected fromthe group consisting of —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —C(O)—, —CH₂C(O)—,—C(O)CH₂—, —CH₂—C(O)CH₂—, —C(O)CH₂CH₂—, —CH₂CH₂C(O)—, —O—, —OCH₂—,—CH₂O—, —CH₂OCH₂—, —OCH₂CH₂—, —CH₂CH₂O—, —N(CH₃)—, —NHCH₂—, —CH₂NH—,—CH₂NHCH₂—, —NHCH₂CH₂—, —CH₂CH₂NH—, —NH—C(O)—, —NCH₃—C(O)—, —C(O)NH—,—C(O)NCH₃—, —NHC(O)CH₂—, —C(O)NHCH₂—, —C(O)CH₂NH—, —CH₂NHC(O)—,—CH₂C(O)NH—, —NHCH₂C(O)—, —S—, —SCH₂—, —CH₂S—, —SCH₂CH₂—, —CH₂SCH₂—,—CH₂CH₂S—, —C(O)S—, —C(O)SCH₂—, —CH₂C(O)S—, —C(O)CH₂S—, and —CH₂SC(O)—,each substituted or unsubstituted.

In another particular variation of the above embodiments, L is selectedfrom the group consisting of —CH₂—, —C(O)—, —CH₂C(O)—, —C(O)CH₂—,—CH₂—C(O)CH₂—, —C(O)CH₂CH₂—, and —CH₂CH₂C(O)—, each substituted orunsubstituted.

In one particular variation of the above embodiments, -L-X takentogether is selected from the group consisting of—(CH₂)-(2-cyano)phenyl; —(CH₂)-(3-cyano)phenyl;—(CH₂)-(2-hydroxy)phenyl; —(CH₂)-(3-hydroxy)phenyl;—(CH₂)-(2-alkenyl)phenyl; —(CH₂)-(3-alkenyl)phenyl;—(CH₂)-(2-alkynyl)phenyl; —(CH₂)-(3-alkynyl)phenyl;—(CH₂)-(2-methoxy)phenyl; —(CH₂)-(3-methoxy)phenyl;—(CH₂)-(2-nitro)phenyl; —(CH₂)-(3-nitro)phenyl;—(CH₂)-(2-carboxy)phenyl; —(CH₂)-(3-carboxy)phenyl;—(CH₂)-(2-carboxamido)phenyl; —(CH₂)-(3-carboxamido)phenyl;—(CH₂)-(2-sulfonamido)phenyl; —(CH₂)-(3-sulfonamido)phenyl;—(CH₂)-(2-tetrazolyl)phenyl; —(CH₂)-(3-tetrazolyl)phenyl;—(CH₂)-(2-aminomethyl)phenyl; —(CH₂)-(3-aminomethyl)phenyl;—(CH₂)-(2-hydroxymethyl)phenyl; —(CH₂)-(3-hydroxymethyl)phenyl;—(CH₂)-(2-phenyl)phenyl; —(CH₂)-(3-phenyl)phenyl; —(CH₂)-(2-halo)phenyl;—(CH₂)-(3-halo)phenyl; —(CH₂)-(2-CONH₂)phenyl; —(CH₂)-(3-CONH₂)phenyl;—(CH₂)-(2-CONH(C₁₋₇)alkyl)phenyl; —(CH₂)-(3-CONH(C₁₋₇)alkyl)phenyl;—(CH₂)-(2-CO₂(C₁₋₇)alkyl)phenyl; —(CH₂)-(3-CO₂(C₁₋₇)alkyl)phenyl;—(CH₂)-(2-NH₂)phenyl; —(CH₂)-(3-NH₂)phenyl;—(CH₂)-(2-(C₃₋₇)alkyl)phenyl; —(CH₂)-(3-(C₃₋₇)alkyl)phenyl;—(CH₂)-(2-(C₃₋₇)cycloalkyl)phenyl; —(CH₂)-(3-(C₃₋₇)cycloalkyl)phenyl;—(CH₂)-(2-aryl)phenyl; —(CH₂)-(3-aryl)phenyl;—(CH₂)-(2-heteroaryl)phenyl; —(CH₂)-(3-heteroaryl)phenyl;—(CH₂)-2-bromo-5-fluoro phenyl; —(CH₂)-2-chloro-5-fluoro phenyl;—(CH₂)-2-cyano-5-fluoro phenyl; —(CH₂)-2,5-dichloro phenyl;—(CH₂)-2,5-difluoro phenyl; —(CH₂)-2,5-dibromo phenyl;—(CH₂)-2-bromo-3,5-difluoro phenyl; —(CH₂)-2-chloro-3,5-difluoro phenyl;—(CH₂)-2,3,5-trifluoro phenyl; —(CH₂)-2,3,5,6-tetrafluorophenyl;—(CH₂)-2-bromo-3,5,6-trifluoro phenyl; —(CH₂)-2-chloro-3,5,6-trifluorophenyl; —(CH₂)-2-cyano-3,5-difluoro phenyl;—(CH₂)-2-cyano-3,5,6-trifluoro phenyl;—(CH₂)-(2-heterocycloalkyl)phenyl; and—(CH₂)-(3-heterocycloalkyl)phenyl, each substituted or unsubstituted.

In another embodiment, DPP-IV inhibitors of the present inventioninclude compounds comprising:

wherein

n is 1, 2, or 3;

M is N or CR₄;

Q¹ and Q² are each independently selected from the group consisting ofCO, CS, SO, SO₂, and C═NR₉;

R₂ is hydrogen or selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,hetero(C₄₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted;

R₃ is selected from the group consisting of perhalo(C₁₋₁₀)alkyl, amino,(C₁₋₁₀)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,aryl, heteroaryl, carbonyl (C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl,sulfonyl (C₁₋₃)alkyl, sulfinyl (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted, and asubstituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;

R₄ is hydrogen or is selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, amino, cyano, thio, (C₁₋₁₀)alkyl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy,carbonyl group, imino group, sulfonyl group and sulfinyl group, eachsubstituted or unsubstituted;

each R₅ and R₆ is independently hydrogen or is selected from the groupconsisting of a substituted or unsubstituted (C₁₋₁₀)alkyl, a substitutedor unsubstituted (C₁₋₁₀)alkoxy, cyano, and halo, or where R₅ and R₆ aretaken together to form a ring;

R₉ is hydrogen or is selected from the group consisting of alkyl,cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl,and heterobicycloaryl, each substituted or unsubstituted; and

X is selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl,carbonyl (C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl,sulfinyl (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl,hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonylgroup, cyano, imino group, sulfonyl group and sulfinyl group, eachsubstituted or unsubstituted.

Substituent X:

In regard to particular variations of the present invention, there isprovided compounds wherein X is a substituted or unsubstituted(C₃₋₇)cycloalkyl. According to each of the above variations, theinvention provides compounds wherein X is a substituted or unsubstituted(C₃₋₇)heterocycloalkyl, or wherein X is a substituted or unsubstitutedaryl.

Further, according to each of the above variations, the inventionprovides compounds wherein X is a substituted or unsubstituted phenyl,or wherein X is a substituted or unsubstituted heteroaryl. In anothervariation according to the above variation, X is a ring having anon-hydrogen substituent at a 2 or 3 position of the ring.

According to the above variations, there is provided compounds wherein Xis a ring having a non-hydrogen substituent at a 2 or 3 position of thering selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl,carbonyl (C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl,sulfinyl (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl,hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, cyano, nitro,halo, imino group, sulfonyl group and sulfinyl group, each substitutedor unsubstituted. In another variation of the above, X is a substitutedor unsubstituted halophenyl or dihalophenyl. In yet another variation, Xis a substituted or unsubstituted haloaryl, haloheteroaryl, dihaloarylor dihaloheteroaryl.

According to the above variations, X is selected from the groupconsisting of (2-cyano)phenyl; (3-cyano)phenyl; (2-hydroxy)phenyl;(3-hydroxy)phenyl; (2-alkenyl)phenyl; (3-alkenyl)phenyl;(2-alkynyl)phenyl; (3-alkynyl)phenyl; (2-methoxy)phenyl;(3-methoxy)phenyl; (2-nitro)phenyl; (3-nitro)phenyl; (2-carboxy)phenyl;(3-carboxy)phenyl; —(CH₂)-(2-carboxamido)phenyl; (3-carboxamido)phenyl;(2-sulfonamido)phenyl; (3-sulfonamido)phenyl; (2-tetrazolyl)phenyl;(3-tetrazolyl)phenyl; (2-aminomethyl)phenyl; (3-aminomethyl)phenyl;(2-hydroxymethyl)phenyl; (3-hydroxymethyl)phenyl; (2-phenyl)phenyl;(3-phenyl)phenyl; (2-halo)phenyl; (3-halo)phenyl; (2-CONH₂)phenyl;(3-CONH₂)phenyl; (2-CONH(C₁₋₇)alkyl)phenyl; (3-CONH(C₁₋₇)alkyl)phenyl;(2-CO₂(C₁₋₇)alkyl)phenyl; (3-CO₂(C₁₋₇)alkyl)phenyl; (2-NH₂)phenyl;(3-NH₂)phenyl; (2-(C₃₋₇)alkyl)phenyl; (3-(C₃₋₇)alkyl)phenyl;(2-(C₃₋₇)cycloalkyl)phenyl; (3-(C₃₋₇)cycloalkyl)phenyl; (2-aryl)phenyl;(3-aryl)phenyl; (2-heteroaryl)phenyl; (3-heteroaryl)phenyl;2-bromo-5-fluoro phenyl; 2-chloro-5-fluoro phenyl; 2-cyano-5-fluorophenyl; 2,5-dichloro phenyl; 2,5-difluoro phenyl; 2,5-dibromo phenyl;2-bromo-3,5-difluoro phenyl; 2-chloro-3,5-difluoro phenyl;2,3,5-trifluoro phenyl; 2,3,5,6-tetrafluorophenyl;2-bromo-3,5,6-trifluoro phenyl; 2-chloro-3,5,6-trifluoro phenyl;2-cyano-3,5-difluoro phenyl; 2-cyano-3,5,6-trifluoro phenyl;(2-heterocycloalkyl)phenyl; and (3-heterocycloalkyl)phenyl, eachsubstituted or unsubstituted.

In regard to the above particular variations, the invention also includecompounds wherein X is selected from the group consisting of

wherein

A is S, O or NR₂₄;

B is CR₂₃ or N;

R₂₃ is independently selected from the group consisting of hydrogen,halo, perhalo(C₁₋₁₀)alkyl, amino, thio, cyano, CF₃, nitro, (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl, hetero(C₈₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, imino group, carbonyl group,aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, andsulfinyl group, each substituted or unsubstituted; and

R₂₄ is independently selected from the group consisting of hydrogen,perhalo(C₁₋₁₀)alkyl, amino, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl (C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, hetero(C₈₋₁₂)bicycloaryl, carbonyl (C₁₋₃)alkyl,thiocarbonyl (C₁₋₃)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,heteroaryloxy, imino group, carbonyl group, aminosulfonyl,alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, and sulfinyl group,each substituted or unsubstituted.

In one variation of the above embodiments and variations, X is selectedfrom the group consisting of

wherein

t is 0, 1, 2, 3, 4 or 5; and

each R₇ is independently selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, CF₃, (C₁₋₁₀)alkyl, alkenyl, alkynyl, aryl,heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl,cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy,alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group,each substituted or unsubstituted.

In another variation of the above compounds, X is selected from thegroup consisting of

wherein

s is 0, 1, 2, or 3; and

each R₇ is independently selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, CF₃, (C₁₋₁₀)alkyl, alkenyl, alkynyl, aryl,heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl,cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy,alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group,each substituted or unsubstituted.

In one particular variation of the above compounds, R₇ is independentlyselected from the group consisting of -cyano, -methoxy, -nitro,-carboxy, -sulfonamido, -tetrazolyl, -aminomethyl, -hydroxymethyl,-phenyl, -halo, —CONH₂, —CONH(C₁₋₇)alkyl, —CO₂(C₁₋₇)alkyl, —NH₂, —OH,—(C₁₋₅)alkyl, -alkenyl, -alkynyl, (C₁₋₅)cycloalkyl, aryl, heteroaryl,and heterocycloalkyl, each substituted or unsubstituted.

In another embodiment, DPP-IV inhibitors of the present inventioninclude compounds comprising:

wherein

m is 0, 1, 2, 3, 4, or 5;

n is 1, 2, or 3;

M is N or CR₄;

Q¹ and Q² are each independently selected from the group consisting ofCO, CS, SO, SO₂, and C═NR₉;

R₂ is hydrogen or selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,hetero(C₄₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted;

R₃ is selected from the group consisting of perhalo(C₁₋₁₀)alkyl, amino,(C₁₋₁₀)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,aryl, heteroaryl, carbonyl (C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl,sulfonyl (C₁₋₃)alkyl, sulfinyl (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted, and asubstituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;

R₄ is hydrogen or is selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, amino, cyano, thio, (C₁₋₁₀)alkyl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy,carbonyl group, imino group, sulfonyl group and sulfinyl group, eachsubstituted or unsubstituted;

each R₅ and R₆ is independently hydrogen or is selected from the groupconsisting of a substituted or unsubstituted (C₁₋₁₀)alkyl, a substitutedor unsubstituted (C₁₋₁₀)alkoxy, cyano, and halo, or where R₅ and R₆ aretaken together to form a ring;

each R₇ is independently selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, CF₃, (C₁₋₁₀)alkyl, alkenyl, alkynyl, aryl,heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl,cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy,alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group,each substituted or unsubstituted; and

R₉ is hydrogen or is selected from the group consisting of alkyl,cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl,and heterobicycloaryl, each substituted or unsubstituted.

In another embodiment, DPP-IV inhibitors of the present inventioninclude compounds comprising:

a member selected from the group consisting of

wherein

n is 1, 2, or 3;

M is N or CR₄;

each of T, U, V, W and Y is independently nitrogen or CR₁₆, providedthat no more than two of T, U, V, W and Y are nitrogen;

Q¹ and Q² are each independently selected from the group consisting ofCO, CS, SO, SO₂, and C═NR₉;

R₂ is hydrogen or selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,hetero(C₄₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted;

R₃ is selected from the group consisting of perhalo(C₁₋₁₀)alkyl, amino,(C₁₋₁₀)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,aryl, heteroaryl, carbonyl (C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl,sulfonyl (C₁₋₃)alkyl, sulfinyl (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted, and asubstituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;

R₄ is hydrogen or is selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, amino, cyano, thio, (C₁₋₁₀)alkyl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy,carbonyl group, imino group, sulfonyl group and sulfinyl group, eachsubstituted or unsubstituted;

each R₅ and R₆ is independently hydrogen or is selected from the groupconsisting of a substituted or unsubstituted (C₁₋₁₀)alkyl, a substitutedor unsubstituted (C₁₋₁₀)alkoxy, cyano, and halo, or where R₅ and R₆ aretaken together to form a ring;

R₉ is hydrogen or is selected from the group consisting of alkyl,cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl,and heterobicycloaryl, each substituted or unsubstituted; and

each R₁₆ is independently selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, CF₃, (C₁₋₁₀)alkyl, alkenyl, alkynyl, aryl,heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl,cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy,alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group,each substituted or unsubstituted.

In another embodiment, DPP-IV inhibitors of the present inventioninclude compounds comprising:

wherein

Q¹ and Q² are each independently selected from the group consisting ofCO, CS, SO, SO₂, and C═NR₉;

R₁ is hydrogen or is selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, amino, cyano, thio, (C₁₋₁₀)alkyl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy,carbonyl group, imino group, sulfonyl group and sulfinyl group, eachsubstituted or unsubstituted;

R₂ is hydrogen or selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,hetero(C₄₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted;

R₃ is selected from the group consisting of perhalo(C₁₋₁₀)alkyl, amino,(C₁₋₁₀)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,aryl, heteroaryl, carbonyl (C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl,sulfonyl (C₁₋₃)alkyl, sulfinyl (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted, and asubstituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;

R₉ is hydrogen or is selected from the group consisting of alkyl,cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl,and heterobicycloaryl, each substituted or unsubstituted;

L is a linker providing 1, 2 or 3 atom separation between X and the ringto which L is attached, wherein the atoms of the linker providing theseparation are selected from the group consisting of carbon, oxygen,nitrogen, and sulfur; and

X is selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl,carbonyl (C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl,sulfinyl (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl,hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonylgroup, cyano, imino group, sulfonyl group and sulfinyl group, eachsubstituted or unsubstituted.

In another embodiment, DPP-IV inhibitors of the present inventioninclude compounds comprising:

wherein

R₁ is hydrogen or is selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, amino, cyano, thio, (C₁₋₁₀)alkyl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy,carbonyl group, imino group, sulfonyl group and sulfinyl group, eachsubstituted or unsubstituted;

R₂ is hydrogen or selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,hetero(C₄₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted;

R₃ is selected from the group consisting of perhalo(C₁₋₁₀)alkyl, amino,(C₁₋₁₀)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,aryl, heteroaryl, carbonyl (C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl,sulfonyl (C₁₋₃)alkyl, sulfinyl (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted, and asubstituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;

L is a linker providing 1, 2 or 3 atom separation between X and the ringto which L is attached, wherein the atoms of the linker providing theseparation are selected from the group consisting of carbon, oxygen,nitrogen, and sulfur; and

X is selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl,carbonyl (C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl,sulfinyl (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl,hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonylgroup, cyano, imino group, sulfonyl group and sulfinyl group, eachsubstituted or unsubstituted.

Substituent L:

In one variation of the present invention, there is provided compoundswherein the 1, 2 or 3 atoms of L providing the separation consist ofcarbon atoms. In another variation, the 1, 2 or 3 atoms of L providingthe separation are selected from the group of linkers consisting of atleast one oxygen or at least one nitrogen atom. In one particularvariation, L separates X from the ring atom by one atom.

In regard to particular variation of the present invention, L isselected from the group consisting of —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—C(O)—, —CH₂C(O)—, —C(O)CH₂—, —CH₂—C(O)CH₂—, —C(O)CH₂CH₂—, —CH₂CH₂C(O)—,—O—, —OCH₂—, —CH₂O—, —CH₂OCH₂—, —OCH₂CH₂—, —CH₂CH₂O—, —N(CH₃)—, —NHCH₂—,—CH₂NH—, —CH₂NHCH₂—, —NHCH₂CH₂—, —CH₂CH₂NH—, —NH—C(O)—, —NCH₃—C(O)—,—C(O)NH—, —C(O)NCH₃—, —NHC(O)CH₂—, —C(O)NHCH₂—, —C(O)CH₂NH—,—CH₂NHC(O)—, —CH₂C(O)NH—, —NHCH₂C(O)—, —S—, —SCH₂—, —CH₂S—, —SCH₂CH₂—,—CH₂SCH₂—, —CH₂CH₂S—, —C(O)S—, —C(O)SCH₂—, —CH₂C(O)S—, —C(O)CH₂S—, and—CH₂SC(O)—, each substituted or unsubstituted.

In regard to another variation of the above compounds, L is selectedfrom the group consisting of —CH₂—, —C(O)—, —CH₂C(O)—, —C(O)CH₂—,—CH₂—C(O)CH₂—, —C(O)CH₂CH₂—, and —CH₂CH₂C(O)—, each substituted orunsubstituted.

In another variation of the above compounds, -L-X taken together isselected from the group consisting of —(CH₂)-(2-cyano)phenyl;—(CH₂)-(3-cyano)phenyl; —(CH₂)-(2-hydroxy)phenyl;—(CH₂)-(3-hydroxy)phenyl; —(CH₂)-(2-alkenyl)phenyl;—(CH₂)-(3-alkenyl)phenyl; —(CH₂)-(2-alkynyl)phenyl;—(CH₂)-(3-alkynyl)phenyl; —(CH₂)-(2-methoxy)phenyl;—(CH₂)-(3-methoxy)phenyl; —(CH₂)-(2-nitro)phenyl;—(CH₂)-(3-nitro)phenyl; —(CH₂)-(2-carboxy)phenyl;—(CH₂)-(3-carboxy)phenyl; —(CH₂)-(2-carboxamido)phenyl;—(CH₂)-(3-carboxamido)phenyl; —(CH₂)-(2-sulfonamido)phenyl;—(CH₂)-(3-sulfonamido)phenyl; —(CH₂)-(2-tetrazolyl)phenyl;—(CH₂)-(3-tetrazolyl)phenyl; —(CH₂)-(2-aminomethyl)phenyl;—(CH₂)-(3-aminomethyl)phenyl; —(CH₂)-(2-hydroxymethyl)phenyl;—(CH₂)-(3-hydroxymethyl)phenyl; —(CH₂)-(2-phenyl)phenyl;—(CH₂)-(3-phenyl)phenyl; —(CH₂)-(2-halo)phenyl; —(CH₂)-(3-halo)phenyl;—(CH₂)-(2-CONH₂)phenyl; —(CH₂)-(3-CONH₂)phenyl;—(CH₂)-(2-CONH(C₁₋₇)alkyl)phenyl; —(CH₂)-(3-CONH(C₁₋₇)alkyl)phenyl;—(CH₂)-(2-CO₂(C₁₋₇)alkyl)phenyl; —(CH₂)-(3-CO₂(C₁₋₇)alkyl)phenyl;—(CH₂)-(2-NH₂)phenyl; —(CH₂)-(3-NH₂)phenyl;—(CH₂)-(2-(C₃₋₇)alkyl)phenyl; —(CH₂)-(3-(C₃₋₇)alkyl)phenyl;—(CH₂)-(2-(C₃₋₇)cycloalkyl)phenyl; —(CH₂)-(3-(C₃₋₇)cycloalkyl)phenyl;—(CH₂)-(2-aryl)phenyl; —(CH₂)-(3-aryl)phenyl;—(CH₂)-(2-heteroaryl)phenyl; —(CH₂)-(3-heteroaryl)phenyl;—(CH₂)-2-bromo-5-fluoro phenyl; —(CH₂)-2-chloro-5-fluoro phenyl;—(CH₂)-2-cyano-5-fluoro phenyl; —(CH₂)-2,5-dichloro phenyl;—(CH₂)-2,5-difluoro phenyl; —(CH₂)-2,5-dibromo phenyl;—(CH₂)-2-bromo-3,5-difluoro phenyl; —(CH₂)-2-chloro-3,5-difluoro phenyl;—(CH₂)-2,3,5-trifluoro phenyl; —(CH₂)-2,3,5,6-tetrafluorophenyl;—(CH₂)-2-bromo-3,5,6-trifluoro phenyl; —(CH₂)-2-chloro-3,5,6-trifluorophenyl; —(CH₂)-2-cyano-3,5-difluoro phenyl;—(CH₂)-2-cyano-3,5,6-trifluoro phenyl;—(CH₂)-(2-heterocycloalkyl)phenyl; and—(CH₂)-(3-heterocycloalkyl)phenyl, each substituted or unsubstituted.

In another embodiment, DPP-IV inhibitors of the present inventioninclude compounds comprising:

wherein

n is 1, 2, or 3;

Q¹ and Q² are each independently selected from the group consisting ofCO, CS, SO, SO₂, and C═NR₉;

R₁ is hydrogen or is selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, amino, cyano, thio, (C₁₋₁₀)alkyl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy,carbonyl group, imino group, sulfonyl group and sulfinyl group, eachsubstituted or unsubstituted;

R₂ is hydrogen or selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,hetero(C₄₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted;

R₃ is selected from the group consisting of perhalo(C₁₋₁₀)alkyl, amino,(C₁₋₁₀)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,aryl, heteroaryl, carbonyl (C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl,sulfonyl (C₁₋₃)alkyl, sulfinyl (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted, and asubstituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;

each R₅ and R₆ is independently hydrogen or is selected from the groupconsisting of a substituted or unsubstituted (C₁₋₁₀)alkyl, a substitutedor unsubstituted (C₁₋₁₀)alkoxy, cyano, and halo, or where R₅ and R₆ aretaken together to form a ring;

R₉ is hydrogen or is selected from the group consisting of alkyl,cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl,and heterobicycloaryl, each substituted or unsubstituted; and

X is selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl,carbonyl (C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl,sulfinyl (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl,hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonylgroup, cyano, imino group, sulfonyl group and sulfinyl group, eachsubstituted or unsubstituted.

Substituent X:

According to the above variations, the invention provides compoundswherein X is a substituted or unsubstituted (C₃₋₇)cycloalkyl. In anotherparticular variation of the above compounds, wherein X is a substitutedor unsubstituted (C₃₋₇)heterocycloalkyl, wherein X is a substituted orunsubstituted aryl, or wherein X is a substituted or unsubstitutedphenyl. In another particular variation, X is a substituted orunsubstituted heteroaryl.

In one particular variation of the above compounds, X is a ring having anon-hydrogen substituent at a 2 or 3 position of the ring. In onevariation of the above compounds, X is a ring having a non-hydrogensubstituent at a 2 or 3 position of the ring selected from the groupconsisting of (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,hetero(C₄₋₁₂)bicycloaryl, carbonyl (C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl (C₁₋₃)alkyl, imino(C₁₋₃)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,heteroaryloxy, carbonyl group, cyano, nitro, halo, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted.

In another particular variation, X is a substituted or unsubstitutedhalophenyl or dihalophenyl. In yet another particular variation, thereis provided compounds wherein X is a substituted or unsubstitutedhaloaryl, haloheteroaryl, dihaloaryl or dihaloheteroaryl.

In regard to particular variations, the present invention providescompounds wherein X is selected from the group consisting of(2-cyano)phenyl; (3-cyano)phenyl; (2-hydroxy)phenyl; (3-hydroxy)phenyl;(2-alkenyl)phenyl; (3-alkenyl)phenyl; (2-alkynyl)phenyl;(3-alkynyl)phenyl; (2-methoxy)phenyl; (3-methoxy)phenyl;(2-nitro)phenyl; (3-nitro)phenyl; (2-carboxy)phenyl; (3-carboxy)phenyl;—(CH₂)-(2-carboxamido)phenyl; (3-carboxamido)phenyl;(2-sulfonamido)phenyl; (3-sulfonamido)phenyl; (2-tetrazolyl)phenyl;(3-tetrazolyl)phenyl; (2-aminomethyl)phenyl; (3-aminomethyl)phenyl;(2-hydroxymethyl)phenyl; (3-hydroxymethyl)phenyl; (2-phenyl)phenyl;(3-phenyl)phenyl; (2-halo)phenyl; (3-halo)phenyl; (2-CONH₂)phenyl;(3-CONH₂)phenyl; (2-CONH(C₁₋₇)alkyl)phenyl; (3-CONH(C₁₋₇)alkyl)phenyl;(2-CO₂(C₁₋₇)alkyl)phenyl; (3-CO₂(C₁₋₇)alkyl)phenyl; (2-NH₂)phenyl;(3-NH₂)phenyl; (2-(C₃₋₇)alkyl)phenyl; (3-(C₃₋₇)alkyl)phenyl;(2-(C₃₋₇)cycloalkyl)phenyl; (3-(C₃₋₇)cycloalkyl)phenyl; (2-aryl)phenyl;(3-aryl)phenyl; (2-heteroaryl)phenyl; (3-heteroaryl)phenyl;2-bromo-5-fluoro phenyl; 2-chloro-5-fluoro phenyl; 2-cyano-5-fluorophenyl; 2,5-dichloro phenyl; 2,5-difluoro phenyl; 2,5-dibromo phenyl;2-bromo-3,5-difluoro phenyl; 2-chloro-3,5-difluoro phenyl;2,3,5-trifluoro phenyl; 2,3,5,6-tetrafluorophenyl;2-bromo-3,5,6-trifluoro phenyl; 2-chloro-3,5,6-trifluoro phenyl;2-cyano-3,5-difluoro phenyl; 2-cyano-3,5,6-trifluoro phenyl;(2-heterocycloalkyl)phenyl; and (3-heterocycloalkyl)phenyl, eachsubstituted or unsubstituted.

In one variation of the above compounds, X is selected from the groupconsisting of

wherein

A is S, O or NR₂₄;

B is CR₂₃ or N;

R₂₃ is independently selected from the group consisting of hydrogen,halo, perhalo(C₁₋₁₀)alkyl, amino, thio, cyano, CF₃, nitro, (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl, hetero(C₈₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, imino group, carbonyl group,aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, andsulfinyl group, each substituted or unsubstituted; and

R₂₄ is independently selected from the group consisting of hydrogen,perhalo(C₁₋₁₀)alkyl, amino, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl (C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, hetero(C₈₋₁₂)bicycloaryl, carbonyl (C₁₋₃)alkyl,thiocarbonyl (C₁₋₃)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,heteroaryloxy, imino group, carbonyl group, aminosulfonyl,alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, and sulfinyl group,each substituted or unsubstituted.

In another particular variation of the above compounds, X is selectedfrom the group consisting of

wherein

t is 0, 1, 2, 3, 4, or 5; and

each R₇ is independently selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, CF₃, (C₁₋₁₀)alkyl, alkenyl, alkynyl, aryl,heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl,cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy,alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group,each substituted or unsubstituted.

In yet another variation, X is selected from the group consisting of

wherein

s is 0, 1, 2, or 3; and

each R₇ is independently selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, CF₃, (C₁₋₁₀)alkyl, alkenyl, alkynyl, aryl,heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl,cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy,alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group,each substituted or unsubstituted.

In one particular variation of the above compounds, R₇ is independentlyselected from the group consisting of -cyano, -methoxy, -nitro,-carboxy, -sulfonamido, -tetrazolyl, -aminomethyl, -hydroxymethyl,-phenyl, -halo, —CONH₂, —CONH(C₁₋₇)alkyl, —CO₂(C₁₋₇)alkyl, —NH₂, —OH,—(C₁₋₅)alkyl, -alkenyl, -alkynyl, (C₁₋₅)cycloalkyl, aryl, heteroaryl,and heterocycloalkyl, each substituted or unsubstituted.

In another embodiment, DPP-IV inhibitors of the present inventioninclude compounds comprising:

wherein

m is 0, 1, 2, 3, 4 or 5;

n is 1, 2, or 3;

Q¹ and Q² are each independently selected from the group consisting ofCO, CS, SO, SO₂, and C═NR₉;

R₁ is hydrogen or is selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, amino, cyano, thio, (C₁₋₁₀)alkyl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy,carbonyl group, imino group, sulfonyl group and sulfinyl group, eachsubstituted or unsubstituted;

R₂ is hydrogen or selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,hetero(C₄₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted;

R₃ is selected from the group consisting of perhalo(C₁₋₁₀)alkyl, amino,(C₁₋₁₀)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,aryl, heteroaryl, carbonyl (C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl,sulfonyl (C₁₋₃)alkyl, sulfinyl (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted, and asubstituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;

each R₅ and R₆ is independently hydrogen or is selected from the groupconsisting of a substituted or unsubstituted (C₁₋₁₀)alkyl, a substitutedor unsubstituted (C₁₋₁₀)alkoxy, cyano, and halo, or where R₅ and R₆ aretaken together to form a ring;

each R₇ is independently selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, CF₃, (C₁₋₁₀)alkyl, alkenyl, alkynyl, aryl,heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl,cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy,alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group,each substituted or unsubstituted; and

R₉ is hydrogen or is selected from the group consisting of alkyl,cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl,and heterobicycloaryl, each substituted or unsubstituted.

In another embodiment, DPP-IV inhibitors of the present inventioninclude compounds comprising:

a member selected from the group consisting of

wherein

n is 1, 2, or 3;

Q¹ and Q² are each independently selected from the group consisting ofCO, CS, SO, SO₂, and C═NR₉;

each of T, U, V, W and Y is independently nitrogen or CR₁₆, providedthat no more than two of T, U, V, W and Y are nitrogen;

R₁ is hydrogen or is selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, amino, cyano, thio, (C₁₋₁₀)alkyl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy,carbonyl group, imino group, sulfonyl group and sulfinyl group, eachsubstituted or unsubstituted;

R₂ is hydrogen or selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,hetero(C₄₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted;

R₃ is selected from the group consisting of perhalo(C₁₋₁₀)alkyl, amino,(C₁₋₁₀)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,aryl, heteroaryl, carbonyl (C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl,sulfonyl (C₁₋₃)alkyl, sulfinyl (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted, and asubstituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;

each R₅ and R₆ is independently hydrogen or is selected from the groupconsisting of a substituted or unsubstituted (C₁₋₁₀)alkyl, a substitutedor unsubstituted (C₁₋₁₀)alkoxy, cyano, and halo, or where R₅ and R₆ aretaken together to form a ring;

R₉ is hydrogen or is selected from the group consisting of alkyl,cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, bicycloaryl,and heterobicycloaryl, each substituted or unsubstituted; and

each R₁₆ is independently selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, CF₃, (C₁₋₁₀)alkyl, alkenyl, alkynyl, aryl,heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl,cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy,alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group,each substituted or unsubstituted.

Substituent R₃:

In regard to each of the above embodiments and variations, the presentinvention provides compounds wherein R₃ is selected from the groupconsisting of amino, (C₁₋₁₀)alkyl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, aryl, and heteroaryl, each substituted orunsubstituted, and a substituted or unsubstituted 3, 4, 5, 6 or 7membered ring.

Further, according to each of the above embodiments and variations, thepresent invention also provides compounds wherein R₃ comprises theformula

wherein R₁₀ and R₁₁ are each independently selected from the groupconsisting of hydrogen, perhalo(C₁₋₁₀)alkyl, amino, (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, andsulfinyl group, each substituted or unsubstituted, or R₁₀ and R₁₁ aretaken together to form a 4, 5, 6, or 7 membered ring, each substitutedor unsubstituted.

According to another variation of each of the above embodiments andvariations, R₃ is a substituted or unsubstituted 3, 4, 5, 6, or 7membered ring, wherein R₃ is a substituted or unsubstituted 3, 4, 5, 6,or 7 membered cycloalkyl, or wherein R₃ is a substituted orunsubstituted 4, 5, 6, or 7 membered heterocycloalkyl. In anothervariation of the above, R₃ is a substituted or unsubstituted aryl, orwherein R₃ is a substituted or unsubstituted heteroaryl.

In one particular variation of the above embodiments and variations, R₃is selected from the group consisting of

wherein p is 0-12 and each R₈ is independently selected from the groupconsisting of halo, perhalo(C₁₋₁₀)alkyl, CF₃, cyano, nitro, hydroxy,alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl,cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, iminogroup, sulfonyl group and sulfinyl group, each substituted orunsubstituted.

In another particular variation of the above embodiments and variations,R₃ is selected from the group consisting of

wherein r is 0-13 and each R₈ is independently selected from the groupconsisting of halo, perhalo(C₁₋₁₀)alkyl, CF₃, cyano, nitro, hydroxy,alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl,cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, iminogroup, sulfonyl group and sulfinyl group, each substituted orunsubstituted.

According to each of the above embodiments and variations, DPP-IVinhibitors of the present invention may comprise compounds wherein R₃ isa substituted or unsubstituted heteroaryl selected from the groupconsisting of furan, thiophene, pyrrole, pyrazole, triazole, isoxazole,oxazole, thiazole, isothiazole, oxadiazole, pyridine, pyridazine,pyrimidine, pyrazine, triazine, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, imidazole, benzimidazole, indole,isoindole, quinoline, isoquinoline, cinnoline, quinazoline,naphthyridine, pyridopyridine, quinoxaline, phthalazine, andbenzothiazole, each substituted or unsubstituted.

Further, according to the above embodiments and variations, R₃ may beselected from the group consisting of (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl (C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted. In another variation, R₃ is a substituted orunsubstituted (C₃₋₇)cycloalkyl ring, optionally comprising O, N(O), N,S, SO, SO₂ or a carbonyl group in the ring.

According to each of the above embodiments and variations, R₃ may alsobe substituted such that R₃ comprises a substituent selected from thegroup consisting of a primary, secondary or tertiary amine, aheterocycloalkyl comprising a nitrogen ring atom, and a heteroarylcomprising a nitrogen ring atom.

In particular variations of the present invention, R₃ comprises a basicnitrogen atom that is capable of interacting with a carboxylic acid sidechain of an active site residue of a protein. In one variation, thebasic nitrogen of R₃ is separated from the ring atom to which R₃ isattached by between 1-5 atoms. In another variation, the basic nitrogenatom forms part of a primary, secondary or tertiary amine. In yetanother variation, the basic nitrogen atom is a nitrogen ring atom of aheterocycloalkyl or a heteroaryl.

In one variation of each of the embodiments of the present invention, R₃includes a basic nitrogen that is capable of interacting with acarboxylic acid side chain of a residue in the DP-4 active site and thuscontributes to the binding affinity of the compound to DP-4. Based onco-crystal structures obtained by Applicants, the observed interactionbetween the basic nitrogen substituent and the carboxylic acid appearsto be via hydrogen bonding or by the formation of a salt bridge.

The basic nitrogen of R₃ in this variation that provides the desiredcarboxylic acid side chain interaction is not typically directlyattached to the ring atom to which R₃ is attached. In this regard, thebasic nitrogen may be viewed as a substituent of the overall R₃ moiety.For example, in the case where R₃ is 3-amino-piperidinyl-1-yl, the basicnitrogen is the 3-amino group and not the nitrogen of the piperidinering. Thus, R₃ may be viewed as a substituted piperidine ring furthercomprising an amine as a basic nitrogen substituent. In a particularvariation, the basic nitrogen of R₃ is optionally separated from thering atom to which R₃ is attached by between 1-5 atoms.

The basic nitrogen atom moiety of R₃ may optionally be selected from thegroup consisting of a primary, secondary or tertiary amine, aheterocycloalkyl comprising a nitrogen ring atom, a heteroarylcomprising a nitrogen ring atom, as well as other nitrogen containingmoieties where the nitrogen can act as a Lewis base. In addition tobasic nitrogen containing moieties, it is envisioned that other Lewisbases, such as oxygen with basic lone pairs, may be capable ofinteracting with a carboxylic acid side chain of a residue in the DP-4active site.

In certain embodiments, R₃ is said to be further substituted with one ormore R₈ substituents. It is noted that at least one of the R₈substituents may comprise the basic nitrogen atom capable of providingthe interaction with the carboxylic acid side chain. In this regard, R₈may optionally comprise a moiety selected from the group consisting of aprimary, secondary or tertiary amine, a heterocycloalkyl comprising anitrogen ring atom, a heteroaryl comprising a nitrogen ring atom, aswell as other nitrogen containing moieties where the nitrogen can act asa Lewis base.

Particular examples of moieties with basic nitrogens according to thisvariation include, but are not limited to —NH₂, —NH(C₁₋₅ alkyl), —N(C₁₋₅alkyl)₂, piperazine, imidazole, and pyridine. Additional particular R₃groups that comprise a basic nitrogen include, but are not limited to3-amino-piperidinyl-1-yl, 3-aminomethyl-pyrrolidin-1-yl,3-aminoazetidin-1-yl, 3-amino-3-methylpiperidin-1-yl,3-aminocyclopent-1-yl, 3-aminomethylcyclopent-1-yl,3-aminomethylcyclohex-1-yl, 3-aminohexahydroazepin-1-yl,3-amino-cyclohex-1-yl, piperazin-1-yl, homopiperazin-1-yl,3-amino-pyrrolidin-1-yl, R-3-aminopiperidin-1-yl,R-3-amino-3-methylpiperidin-1-yl, 3-amino-cyclohex-1-yl,3-amino-cyclopent-1-yl, and 3-amino-pyrrolidin-1-yl, each optionallyfurther substituted.

In regard to a particular variation, at least one R₈ comprises a basicnitrogen atom that is capable of interacting with a carboxylic acid sidechain of an active site residue of a protein. In another particularvariation, the basic nitrogen atom forms part of a primary, secondary ortertiary amine. In another variation of the above compounds, the basicnitrogen atom is a nitrogen ring atom of a heterocycloalkyl comprising anitrogen ring atom or a heteroaryl comprising a nitrogen ring atom.

In one variation of each of the embodiments of the present invention, atleast one R₈ is a primary, secondary or tertiary amine. In anothervariation, at least one R₈ is a substituted or unsubstitutedheterocycloalkyl comprising a nitrogen ring atom or a substituted orunsubstituted heteroaryl comprising a nitrogen ring atom. In yet anotherparticular variation, at least one R₈ is selected from the groupconsisting of —NH₂, —NH(C₁₋₅ alkyl), —N(C₁₋₅ alkyl)₂, piperazine,imidazole, and pyridine.

According to each of the above embodiments and variations, R₃ isselected from the group consisting of 3-amino-piperidinyl-1-yl,3-aminomethyl-pyrrolidin-1-yl, 3-aminoazetidin-1-yl,3-amino-3-methylpiperidin-1-yl, 3-aminocyclopent-1-yl,3-aminomethylcyclopent-1-yl, 3-aminomethylcyclohex-1-yl,3-aminohexahydroazepin-1-yl, 3-amino-cyclohex-1-yl, piperazin-1-yl,homopiperazin-1-yl, 3-amino-pyrrolidin-1-yl, R-3-aminopiperidin-1-yl,R-3-amino-3-methylpiperidin-1-yl, 3-amino-cyclohex-1-yl,3-amino-cyclopent-1-yl, and 3-amino-pyrrolidin-1-yl, each substituted orunsubstituted.

In one particular variation, at least one of Q¹ and Q² is CO. In anothervariation of the above compounds, Q¹ and Q² are CO.

Substituent M:

In another particular variation, the present invention providescompounds wherein M is nitrogen. In yet another particular variation, Mis CR₄ and where R₄ is selected from the group consisting of

wherein

A is S, O or NR₂₄;

B is CR₂₃ or N;

R₂₃ is independently selected from the group consisting of hydrogen,halo, perhalo(C₁₋₁₀)alkyl, amino, thio, cyano, CF₃, nitro, (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl, hetero(C₈₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, imino group, carbonyl group,aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, andsulfinyl group, each substituted or unsubstituted; and

R₂₄ is independently selected from the group consisting of hydrogen,perhalo(C₁₋₁₀)alkyl, amino, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl (C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, hetero(C₈₋₁₂)bicycloaryl, carbonyl (C₁₋₃)alkyl,thiocarbonyl (C₁₋₃)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,heteroaryloxy, imino group, carbonyl group, aminosulfonyl,alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, and sulfinyl group,each substituted or unsubstituted.

In another particular variation, the present invention providescompounds wherein M is CR₄ and where R₄ is selected from the groupconsisting of

wherein u is 0, 1, 2, 3, 4, or 5; and each R₁₈ is independently selectedfrom the group consisting of halo, perhalo(C₁₋₁₀)alkyl, CF₃,(C₁₋₁₀)alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl,alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy,arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio,cyano, nitro, hydroxy, alkoxy, carbonyl group, imine group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted.

In yet another variation, there is provided compounds wherein M is CR₄and where R₄ is selected from the group consisting of

wherein s is 0, 1, 2, or 3; and each R₇ is independently selected fromthe group consisting of halo, perhalo(C₁₋₁₀)alkyl, CF₃, (C₁₋₁₀)alkyl,alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl,heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano,nitro, hydroxy, alkoxy, carbonyl group, imino group, sulfonyl group andsulfinyl group, each substituted or unsubstituted.Substituent R₅ and R₆:

In particular variations of the present invention, there is providedcompounds wherein R₅ and R₆ are hydrogen. In yet another variation, R₅and R₆ are taken together to form a ring. In yet another variation, atleast one of R₅ and R₆ is a halide, such as fluorine.

In another variation of the invention, there is provided compoundswherein at least one of R₅ and R₆ is a substituted or unsubstituted—(C₁₋₈)alkyleneR₁₃, wherein R₁₃ is selected from the group consisting of(C₃₋₁₂)cycloalkyl, hetero(C₄₋₁₂)cycloalkyl, (C₆₋₁₂)aryl,hetero(C₅₋₁₂)aryl, (C₉₋₁₂)bicycloalkyl, hetero(C₉₋₁₂)bicycloalkyl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted.

In another particular variation of the above compounds, R₅ and R₆ arehydrogen, m is 1 or 2, and each R₇ is independently selected from thegroup consisting of halo, perhalo(C₁₋₁₀)alkyl, CF₃, cyano, nitro,hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl,alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy,arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio,alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group,each substituted or unsubstituted.

In regard to particular variations of the invention, there is providedcompounds wherein two R₇ are taken together to form a substituted orunsubstituted fused or bridged ring.

In yet another particular variation, there is provided compounds whereinn is 1, 2 or 3; and R₅ and R₆ are hydrogen. In another variation, n is 1or 2; R₃ is selected from the group consisting of amino, alkoxy,aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group andsulfinyl group, and a substituted or unsubstituted 4, 5, 6 or 7 memberedring; and R₅ and R₆ are hydrogen.

In one particular variation of the above compounds, R₅ and R₆ arehydrogen and R₇ is 2-cyano. In another variation of the above compound,n is 1. In yet another particular variation of the above compounds, n is1, 2 or 3; R₅ and R₆ are hydrogen; and R₃ is selected from the groupconsisting of (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,aryl(C₁₋₁₀)alkyl, heteroaryl (C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

According to particular variation of the above compounds, n is 1, 2 or3; R₅ and R₆ are hydrogen; and each R₇ is independently selected fromthe group consisting of halo, perhalo(C₁₋₁₀)alkyl, alkenyl, alkynyl,CF₃, cyano, nitro, hydroxy, heteroaryl, aryloxy, heteroaryloxy, alkoxy,carbonyl group, imino group, sulfonyl group and sulfinyl group, eachsubstituted or unsubstituted.

Substituent R₇:

In particular variations of the above, there is provided compoundswherein two R₇ are taken together to form a substituted or unsubstitutedfused ring. In another particular variation, two R₇ are taken togetherto form a substituted or unsubstituted bridged ring.

According to particular variations of the above compounds, two of T, U,V, W and Y are taken together and substituted through availablevalencies to form a substituted or unsubstituted ring fused or bridgedto the ring formed by T U, V, W and Y.

Substituent R₂:

According to each of the above embodiments and variations, the presentinvention provides compounds wherein R₂ is a substituted orunsubstituted (C₁₋₁₀)alkyl. In another variation, R₂ is a substituted orunsubstituted (C₁₋₄)alkyl. In yet another variation, R₂ is —Y-Z whereinY a linker providing 1, 2 or 3 atom separation between Z and the ring towhich Y is attached, wherein the atoms of the linker providing theseparation are selected from the group consisting of carbon, oxygen,nitrogen, and sulfur; and Z is hydrogen or selected from the groupconsisting of (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,hetero(C₄₋₁₂)bicycloaryl, carbonyl (C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl (C₁₋₃)alkyl, imino(C₁₋₃)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,heteroaryloxy, alkenyl, alkynyl, carbonyl group, cyano, imino group,sulfonyl group and sulfinyl group, each substituted or unsubstituted.

In yet another variation, R₂ is selected from the group consisting of

wherein A is S, O or NR₂₄; B is CR₂₃ or N; R₂₃ is independently selectedfrom the group consisting of hydrogen, halo, perhalo(C₁₋₁₀)alkyl, amino,thio, cyano, CF₃, nitro, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl (C₁₋₅)alkyl,(C₉₋₁₂)bicycloaryl, hetero(C₈₋₁₂)bicycloaryl, carbonyl (C₁₋₃)alkyl,thiocarbonyl (C₁₋₃)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,heteroaryloxy, imino group, carbonyl group, aminosulfonyl,alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, and sulfinyl group,each substituted or unsubstituted; and R₂₄ is independently selectedfrom the group consisting of hydrogen, perhalo(C₁₋₁₀)alkyl, amino,(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,aryl(C₁₋₁₀)alkyl, heteroaryl (C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,hetero(C₈₋₁₂)bicycloaryl, carbonyl (C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy,imino group, carbonyl group, aminosulfonyl, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, and sulfinyl group, each substituted orunsubstituted.

In yet another variation, R₂ is selected from the group consisting of

wherein t is 0, 1, 2, 3, 4, or 5; and each R₁₈ is independently selectedfrom the group consisting of halo, perhalo(C₁₋₁₀)alkyl, CF₃,(C₁₋₁₀)alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl,alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy,arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio,cyano, nitro, hydroxy, alkoxy, carbonyl group, imine group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted.

Particular examples of DPP-IV inhibitors according to the presentinvention include, but are not limited to:

-   2-(6-Chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile;-   2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile;-   2-{6-[3-Amino-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3-Amino-piperidin-1-yl]-3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3-Amino-piperidin-1-yl]-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3-Amino-piperidin-1-yl]-5-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   6-[3-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-1H-pyrimidine-2,4-dione;-   6-[3-Amino-piperidin-1-yl]-1-(2-iodo-benzyl)-1H-pyrimidine-2,4-dione;-   6-[3-Amino-piperidin-1-yl]-1-(2-bromo-5-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   6-[3-Amino-piperidin-1-yl]-1-(2-chloro-5-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   6-[3-Amino-piperidin-1-yl]-1-(2-chloro-4-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   6-[3-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   2-{6-[Azepan-3(±)-ylamino]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile    (14);-   2-{6-[3(±)-Amino-azepan-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-[6-(2-Amino-ethylamino)-3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-benzonitrile;-   2-{6-[3-Amino-piperidin-1-yl]-3-(3-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3-Amino-piperidin-1-yl]-3-(4-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   [6-(3-Amino-piperidin-1-yl)-3-(1H-benzoimidazol-2-ylmethyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-benzonitrile;-   2-{6-[3-Amino-piperidin-1-yl]-2,4-dioxo-3-(4-pyrazol-1-yl-benzyl)-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3-Amino-piperidin-1-yl]-2,4-dioxo-3-(3-pyrrol-1-yl-benzyl)-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   6-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl]-thiophene-3-carbonitrile;-   3-{4-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl}-benzoic    acid methyl ester;-   3-{4-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl}-benzoic    acid;-   6-[3-Amino-piperidin-1-yl]-1,3-bis-(2-bromo-5-fluoro-benzyl)-1H-pyrimidine-2,4-dione;-   2-{6-[3(R)-Amino-piperidin-1-yl]-5-chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   6-[3(R)-Amino-piperidin-1-yl]-1-(2,5-di-chloro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   6-[3(R)-Amino-piperidin-1-yl]-1-(2-chloro-3,6-di-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   (R)-2-((6-(3-amino-3-methylpiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrile;    and-   2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile.

Particular examples of DPP-IV inhibitors according to the presentinvention further include:

-   2-{6-[3(R)-Amino-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3(R)-Amino-piperidin-1-yl]-3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3(R)-Amino-piperidin-1-yl]-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   {6-[3(R)-Amino-piperidin-1-yl]-5-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   6-[3(R)-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-1H-pyrimidine-2,4-dione;-   6-[3(R)-Amino-piperidin-1-yl]-1-(2-iodo-benzyl)-1H-pyrimidine-2,4-dione;-   6-[3(R)-Amino-piperidin-1-yl]-1-(2-bromo-5-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   6-[3(R)-Amino-piperidin-1-yl]-1-(2-chloro-5-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   6-[3(R)-Amino-piperidin-1-yl]-1-(2-chloro-4-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   6-[3(R)-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   2-{6-[3(R)-Amino-piperidin-1-yl]-3-(3-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3(R)-Amino-piperidin-1-yl]-3-(4-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-[6-(3-Amino-piperidin-1-yl)-3-(1H-benzoimidazol-2-ylmethyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-benzonitrile-   2-{6-[3(R)-Amino-piperidin-1-yl]-2,4-dioxo-3-(4-pyrazol-1-yl-benzyl)-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3(R)-Amino-piperidin-1-yl]-2,4-dioxo-3-(3-pyrrol-1-yl-benzyl)-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   6-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl]-thiophene-3-carbonitrile;-   3-{4-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl}-benzoic    acid methyl ester;-   3-{4-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl}-benzoic    acid;-   6-[3(R)-Amino-piperidin-1-yl]-1,3-bis-(2-bromo-5-fluoro-benzyl)-1H-pyrimidine-2,4-dione;    and-   [6-(3(R)-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile.

In another embodiment, the present invention provides the compounds inthe form of a pharmaceutically acceptable salt.

In yet another embodiment, the present invention provides the compoundspresent in a mixture of stereoisomers. In yet another embodiment, thepresent invention provides the compounds as a single stereoisomer.

In yet another embodiment, the present invention provides pharmaceuticalcompositions comprising the compound as an active ingredient. In yetanother variation, the present invention provides pharmaceuticalcompositions wherein the composition is a solid formulation adapted fororal administration. In yet another particular variation, the presentinvention provides pharmaceutical composition wherein the composition isa tablet. In another particular variation, the present inventionprovides the pharmaceutical composition wherein the composition is aliquid formulation adapted for oral administration. In yet anotherparticular variation, the present invention provides pharmaceuticalcomposition wherein the composition is a liquid formulation adapted forparenteral administration.

In yet another particular variation, the present invention provides thepharmaceutical composition comprising the compound of the inventionwherein the composition is adapted for administration by a routeselected from the group consisting of orally, parenterally,intraperitoneally, intravenously, intraarterially, transdermally,sublingually, intramuscularly, rectally, transbuccally, intranasally,liposomally, via inhalation, vaginally, intraoccularly, via localdelivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, and intrathecally.

In another embodiment, the present invention provides a kit comprising acompound of the present invention and instructions which comprise one ormore forms of information selected from the group consisting ofindicating a disease state for which the compound is to be administered,storage information for the compound, dosing information andinstructions regarding how to administer the compound. In anotherembodiment, the present invention provides the kit that comprises thecompound in a multiple dose form.

In another embodiment, the present invention provides an article ofmanufacture comprising a compound of the present invention, andpackaging materials. In another variation, the packaging materialcomprises a container for housing the compound. In yet anothervariation, the invention provides the article of manufacture wherein thecontainer comprises a label indicating one or more members of the groupconsisting of a disease state for which the compound is to beadministered, storage information, dosing information and/orinstructions regarding how to administer the composition.

In another variation, the present invention provides the article ofmanufacture wherein the article of manufacture comprises the compound ina multiple dose form.

In another embodiment, the present invention provides a method ofinhibiting DPP-IV comprising contacting DPP-IV with a compound accordingto the present invention.

In another embodiment, the present invention provides a method ofinhibiting DPP-IV comprising causing a compound according to the presentinvention to be present in a subject in order to inhibit DPP-IV in vivo.

In another embodiment, the present invention provides a method ofinhibiting DPP-IV comprising: administering a first compound to asubject that is converted in vivo to a second compound wherein thesecond compound inhibits DPP-IV in vivo, the second compound being acompound of the present invention.

In another embodiment, the present invention provides therapeutic methodcomprising: administering a compound according to the present inventionto a subject.

In another embodiment, the present invention provides a method oftreating a disease state for which DPP-IV possesses activity thatcontributes to the pathology and/or symptomology of the disease state,the method comprising causing a compound of the present invention to bepresent in a subject in a therapeutically effective amount for thedisease state.

In another embodiment, the present invention provides a method oftreating cancer in a patient in need thereof, comprising administeringto said patient a therapeutically effective amount of a compoundaccording to the present invention.

In another embodiment, the present invention provides a method oftreating a disease where the disease is type I or type II diabetes.

In another embodiment, the present invention provides a method oftreating autoimmune disorders such as, but not limited to, rheumatoidarthritis, psoriasis, and multiple sclerosis in a patient in needthereof, comprising administering to said patient a therapeuticallyeffective amount of a compound according to the present invention.

In yet another embodiment, the present invention provides a method oftreating cancer where the cancer treated is colorectal, prostate,breast, thyroid, skin, lung, or head and neck.

In another embodiment, the present invention provides a method oftreating a condition characterized by inadequate lymphocyte orhemapoietic cell activation or concentration in a patient in needthereof, comprising administering to said patient a therapeuticallyeffective amount of a compound according to the present invention.

In another embodiment, the present invention provides a method oftreating HIV infection in a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount of acompound according to the present invention.

In yet another embodiment, the present invention provides a method oftreating a condition characterized by inadequate lymphocyte orhemapoietic cell activation or concentration in a patient in needthereof, wherein the condition is a side effect of chemotherapy orradiation therapy.

In yet another embodiment, the present invention provides a method oftreating a condition characterized by inadequate lymphocyte orhemapoietic cell activation or concentration in a patient in needthereof, wherein the condition is a result of kidney failure.

In yet another embodiment, the present invention provides a method oftreating a condition characterized by inadequate lymphocyte orhemapoietic cell activation or concentration in a patient in needthereof, wherein the condition is a result of a bone marrow disorder.

In another embodiment, the present invention provides a method oftreating a condition characterized by immunodeficiency symptoms in apatient in need thereof, comprising administering to said patient atherapeutically effective amount of a compound according to the presentinvention.

In yet another embodiment, the present invention provides a process forproducing a pyrimidin-dione of the formula:

wherein

M is N or CR₄;

R₂ is hydrogen or selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,hetero(C₄₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted;

R₃ is selected from the group consisting of perhalo(C₁₋₁₀)alkyl, amino,(C₁₋₁₀)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,aryl, heteroaryl, carbonyl (C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl,sulfonyl (C₁₋₃)alkyl, sulfinyl (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonylgroup and sulfinyl group, each substituted or unsubstituted, and asubstituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;

R₄ is hydrogen or is selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, amino, cyano, thio, (C₁₋₁₀)alkyl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino (C₁₋₃)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy,carbonyl group, imino group, sulfonyl group and sulfinyl group, eachsubstituted or unsubstituted;

L is a linker providing 1, 2 or 3 atom separation between X and the ringto which L is attached, wherein the atoms of the linker providing theseparation are selected from the group consisting of carbon, oxygen,nitrogen, and sulfur; and

X is selected from the group consisting of (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl,carbonyl (C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl,sulfinyl (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl,hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonylgroup, cyano, imino group, sulfonyl group and sulfinyl group, eachsubstituted or unsubstituted;

the process comprising the steps of:

-   -   (i) contacting a compound of the formula A        -   wherein Hal is halogen;    -   with a compound of the formula B        X-L-LG  B        -   wherein LG is a leaving group;        -   L is a linker providing 1, 2 or 3 atom separation between X            and the ring to which L is attached, wherein the atoms of            the linker providing the separation are selected from the            group consisting of carbon, oxygen, nitrogen, and sulfur;            and        -   X is selected from the group consisting of (C₁₋₁₀)alkyl,            (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl,            aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,            hetero(C₄₋₁₂)bicycloaryl, carbonyl (C₁₋₃)alkyl, thiocarbonyl            (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl (C₁₋₃)alkyl,            imino (C₁₋₃)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy,            aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group,            cyano, imino group, sulfonyl group and sulfinyl group, each            substituted or unsubstituted;    -   under conditions sufficient to produce a compound of the formula        C    -   (ii) contacting the compound of formula C with a compound of        formula D        R₂-LG′  D        -   wherein LG′ is a leaving group;    -   under conditions sufficient to produce a compound of the formula        E;        -   wherein R₂ is selected from the group consisting of            (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,            (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl,            aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,            hetero(C₄₋₁₂)bicycloaryl,            hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, carbonyl (C₁₋₃)alkyl,            thiocarbonyl (C₁₋₃)alkyl, sulfonyl (C₁₋₃)alkyl, sulfinyl            (C₁₋₃)alkyl, imino (C₁₋₃)alkyl, amino, aryl, heteroaryl,            hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group,            imino group, sulfonyl group and sulfinyl group, each            substituted or unsubstituted; and    -   (iii) contacting the compound of formula E with a compound of        formula R₃—H under conditions sufficient to produce the        pyrimidin-dione.

In one variation the pyrimidin-dione product is further converted to anacid addition salt. In particular variations, the acid addition salt isselected from the group consisting of acetate, citrate, hydrochloride,L-lactate, succinate, sulfate, p-toluenesulfonate, benzenesulfonate,benzoate, methanesulfonate, naphthylene-2-sulfonate, propionate,p-toluenesulfonate, hydrobromate, hydroiodate, R-mandelate, andL-tartrate.

In another variation of each of the above embodiments and variations,Hal is selected from the group consisting of Br, Cl and F in thecompound of formula A.

In yet another variation of each of the above embodiments andvariations, the leaving group LG is selected from the group consistingof Br, Cl and I.

In a further variation of each of the above embodiments and variations,step (ii) further comprises the addition of a base. In particularvariations, the base is potassium carbonate.

In still another variation of each of the above embodiments andvariations, product E is further purified before subjecting it to step(iii). In a particular variation, the purification of product E isperformed by solvent washes and/or by chromatography.

In another variation of each of the above embodiments and variations,R₃—H is a secondary amine or an amine hydrochloride. In a particularvariation, R₃—H is selected from the group consisting of

wherein p is 0-12 and each R₈ is independently selected from the groupconsisting of halo, perhalo(C₁₋₁₀)alkyl, CF₃, cyano, nitro, hydroxy,alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl,cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, iminogroup, sulfonyl group and sulfinyl group, each substituted orunsubstituted, or the mono- or di-hydrochloride salt.

In yet another variation of each of the above embodiments andvariations, step iii) further comprises purifying the product by washingthe product with one or more organic solvents or mixtures of solventsand/or by column chromatography.

In a further variation of each of the above embodiments and variations,L is selected from the group consisting of —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—C(O)—, —CH₂C(O)—, —C(O)CH₂—, —CH₂—C(O)CH₂—, —C(O)CH₂CH₂—, —CH₂CH₂C(O)—,—O—, —OCH₂—, —CH₂O—, —CH₂OCH₂—, —OCH₂CH₂—, —CH₂CH₂O—, —N(CH₃)—, —NHCH₂—,—CH₂NH—, —CH₂NHCH₂—, —NHCH₂CH₂—, —CH₂CH₂NH—, —NH—C(O)—, —NCH₃—C(O)—,—C(O)NH—, —C(O)NCH₃—, —NHC(O)CH₂—, —C(O)NHCH₂—, —C(O)CH₂NH—,—CH₂NHC(O)—, —CH₂C(O)NH—, —NHCH₂C(O)—, —S—, —SCH₂—, —CH₂S—, —SCH₂CH₂—,—CH₂SCH₂—, —CH₂CH₂S—, —C(O)S—, —C(O)SCH₂—, —CH₂C(O)S—, —C(O)CH₂S—, and—CH₂SC(O)—, each substituted or unsubstituted. In a particularvariation, L is selected from the group consisting of —CH₂—, —C(O)—,—CH₂C(O)—, —C(O)CH₂—, —CH₂—C(O)CH₂—, —C(O)CH₂CH₂—, and —CH₂CH₂C(O)—,each substituted or unsubstituted.

In still another variation of each of the above embodiments andvariations, -L-X taken together is selected from the group consisting of—(CH₂)-(2-cyano)phenyl; —(CH₂)-(3-cyano)phenyl;—(CH₂)-(2-hydroxy)phenyl; —(CH₂)-(3-hydroxy)phenyl;—(CH₂)-(2-alkenyl)phenyl; —(CH₂)-(3-alkenyl)phenyl;—(CH₂)-(2-alkynyl)phenyl; —(CH₂)-(3-alkynyl)phenyl;—(CH₂)-(2-methoxy)phenyl; —(CH₂)-(3-methoxy)phenyl;—(CH₂)-(2-nitro)phenyl; —(CH₂)-(3-nitro)phenyl;—(CH₂)-(2-carboxy)phenyl; —(CH₂)-(3-carboxy)phenyl;—(CH₂)-(2-carboxamido)phenyl; —(CH₂)-(3-carboxamido)phenyl;—(CH₂)-(2-sulfonamido)phenyl; —(CH₂)-(3-sulfonamido)phenyl;—(CH₂)-(2-tetrazolyl)phenyl; —(CH₂)-(3-tetrazolyl)phenyl;—(CH₂)-(2-aminomethyl)phenyl; —(CH₂)-(3-aminomethyl)phenyl;—(CH₂)-(2-hydroxymethyl)phenyl; —(CH₂)-(3-hydroxymethyl)phenyl;—(CH₂)-(2-phenyl)phenyl; —(CH₂)-(3-phenyl)phenyl; —(CH₂)-(2-halo)phenyl;—(CH₂)-(3-halo)phenyl; —(CH₂)-(2-CONH₂)phenyl; —(CH₂)-(3-CONH₂)phenyl;—(CH₂)-(2-CONH(C₁₋₇)alkyl)phenyl; —(CH₂)-(3-CONH(C₁₋₇)alkyl)phenyl;—(CH₂)-(2-CO₂(C₁₋₇)alkyl)phenyl; —(CH₂)-(3-CO₂(C₁₋₇)alkyl)phenyl;—(CH₂)-(2-NH₂)phenyl; —(CH₂)-(3-NH₂)phenyl;—(CH₂)-(2-(C₃₋₇)alkyl)phenyl; —(CH₂)-(3-(C₃₋₇)alkyl)phenyl;—(CH₂)-(2-(C₃₋₇)cycloalkyl)phenyl; —(CH₂)-(3-(C₃₋₇)cycloalkyl)phenyl;—(CH₂)-(2-aryl)phenyl; —(CH₂)-(3-aryl)phenyl;—(CH₂)-(2-heteroaryl)phenyl; —(CH₂)-(3-heteroaryl)phenyl;—(CH₂)-2-bromo-5-fluoro phenyl; —(CH₂)-2-chloro-5-fluoro phenyl;—(CH₂)-2-cyano-5-fluoro phenyl; —(CH₂)-2,5-dichloro phenyl;—(CH₂)-2,5-difluoro phenyl; —(CH₂)-2,5-dibromo phenyl;—(CH₂)-2-bromo-3,5-difluoro phenyl; —(CH₂)-2-chloro-3,5-difluoro phenyl;—(CH₂)-2,3,5-trifluoro phenyl; —(CH₂)-2,3,5,6-tetrafluorophenyl;—(CH₂)-2-bromo-3,5,6-trifluoro phenyl; —(CH₂)-2-chloro-3,5,6-trifluorophenyl; —(CH₂)-2-cyano-3,5-difluoro phenyl;—(CH₂)-2-cyano-3,5,6-trifluoro phenyl;—(CH₂)-(2-heterocycloalkyl)phenyl; and—(CH₂)-(3-heterocycloalkyl)phenyl, each substituted or unsubstituted.

In a further variation of each of the above embodiments and variations,M is CH, and R₃ comprises the formula

wherein R₁₀ and R₁₁ are each independently selected from the groupconsisting of hydrogen, perhalo(C₁₋₁₀)alkyl, amino, (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl, thiocarbonyl (C₁₋₃)alkyl, aryl, heteroaryl, hydroxy,alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, andsulfinyl group, each substituted or unsubstituted, or R₁₀ and R₁₁ aretaken together to form a 4, 5, 6, or 7 membered ring, each substitutedor unsubstituted.

In yet a further variation, M is CH and R₃ is selected from the groupconsisting of 3-amino-piperidinyl-1-yl, 3-aminomethyl-pyrrolidin-1-yl,2-aminoazetidin-1-yl, 3-amino-3-methylpiperidin-1-yl,3-aminocyclopent-1-yl, 3-aminomethylcyclopent-1-yl,3-aminomethylcyclohex-1-yl, 3-aminohexahydroazepin-1-yl,3-amino-cyclohex-1-yl, piperazin-1-yl, homopiperazin-1-yl,3-amino-pyrrolidin-1-yl, R-3-aminopiperidin-1-yl,R-3-amino-3-methylpiperidin-1-yl, 3-amino-cyclohex-1-yl,3-amino-cyclopent-1-yl, and 3-amino-pyrrolidin-1-yl, each substituted orunsubstituted.

In still a further variation, M is CH and R₂ is a substituted orunsubstituted (C₁₋₁₀)alkyl.

In another of its embodiments, the present invention provides a processfor producing a pyrimidin-dione of the formula

comprising:

-   -   (i) admixing 6-chloro-1H-pyrimidine-2,4-dione with an aryl        halide of the formula        -   where Hal is Br, Cl, or I, under conditions sufficient to            produce a compound of the formula    -   (ii) alkylating the above product with a methyl halide under        conditions sufficient to form a compound of the formula    -   (iii) condensing the above product with a compound of the        formula

In one variation of the above embodiment, the process for producing apyrimidin-dione further comprises the formation of an acid additionsalt. In one particular variation, the acid addition salt is a benzoatesalt.

In another variation of each of the above embodiments and variations,the pyrimidin-dione is selected from the group consisting of:

-   2-(6-Chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile;-   2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile;-   2-{6-[3-Amino-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3-Amino-piperidin-1-yl]-3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3-Amino-piperidin-1-yl]-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3-Amino-piperidin-1-yl]-5-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   6-[3-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-1H-pyrimidine-2,4-dione;-   6-[3-Amino-piperidin-1-yl]-1-(2-iodo-benzyl)-1H-pyrimidine-2,4-dione;-   6-[3-Amino-piperidin-1-yl]-1-(2-bromo-5-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   6-[3-Amino-piperidin-1-yl]-1-(2-chloro-5-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   6-[3-Amino-piperidin-1-yl]-1-(2-chloro-4-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   6-[3-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   2-{6-[Azepan-3    (±)-ylamino]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile    (14);-   2-{6-[3    (±)-Amino-azepan-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   [6-(2-Amino-ethylamino)-3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-benzonitrile;-   2-{6-[3-Amino-piperidin-1-yl]-3-(3-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3-Amino-piperidin-1-yl]-3-(4-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-[6-(3-Amino-piperidin-1-yl)-3-(1H-benzoimidazol-2-ylmethyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-benzonitrile;-   2-{6-[3-Amino-piperidin-1-yl]-2,4-dioxo-3-(4-pyrazol-1-yl-benzyl)-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3-Amino-piperidin-1-yl]-2,4-dioxo-3-(3-pyrrol-1-yl-benzyl)-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   6-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl]-thiophene-3-carbonitrile;-   3-{4-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl}-benzoic    acid methyl ester;-   3-{4-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl}-benzoic    acid;-   2-{6-[3(R)-Amino-piperidin-1-yl]-5-chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   6-[3(R)-Amino-piperidin-1-yl]-1-(2,5-di-chloro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   6-[3(R)-Amino-piperidin-1-yl]-1-(2-chloro-3,6-di-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   (R)-2-((6-(3-amino-3-methylpiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrile;    and-   6-[3-Amino-piperidin-1-yl]-1,3-bis-(2-bromo-5-fluoro-benzyl)-1H-pyrimidine-2,4-dione.

The process of claim 133, wherein the pyrimidin-dione is selected fromthe group consisting of:

-   2-{6-[3(R)-Amino-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3(R)-Amino-piperidin-1-yl]-3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3(R)-Amino-piperidin-1-yl]-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3(R)-Amino-piperidin-1-yl]-5-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   6-[3(R)-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-1H-pyrimidine-2,4-dione;-   6-[3(R)-Amino-piperidin-1-yl]-1-(2-iodo-benzyl)-1H-pyrimidine-2,4-dione;-   6-[3(R)-Amino-piperidin-1-yl]-1-(2-bromo-5-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   6-[3(R)-Amino-piperidin-1-yl]-1-(2-chloro-5-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   6-[3(R)-Amino-piperidin-1-yl]-1-(2-chloro-4-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   6-[3(R)-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;-   2-{6-[3(R)-Amino-piperidin-1-yl]-3-(3-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3(R)-Amino-piperidin-1-yl]-3-(4-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3(R)-Amino-piperidin-1-yl]-2,4-dioxo-3-(4-pyrazol-1-yl-benzyl)-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   2-{6-[3(R)-Amino-piperidin-1-yl]-2,4-dioxo-3-(3-pyrrol-1-yl-benzyl)-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;-   6-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl]-thiophene-3-carbonitrile;-   3-{4-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl}-benzoic    acid methyl ester;-   {4-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl}-benzoic    acid; and-   6-[3(R)-Amino-piperidin-1-yl]-1,3-bis-(2-bromo-5-fluoro-benzyl)-1H-pyrimidine-2,4-dione.

In still another variation of each of the above embodiments andvariations, the pyrimidin-dione is present as a mixture ofstereoisomers. In yet another variation, the pyrimidin-dione comprises asingle stereoisomer.

It is noted in regard to all of the embodiments, and any furtherembodiments, variations, or individual compounds described or claimedherein that all such embodiments, variations, and/or individualcompounds are intended to encompass all pharmaceutical acceptable saltforms whether in the form of a single stereoisomer or mixture ofstereoisomers unless it is specifically specified otherwise. Similarly,when one or more potentially chiral centers are present in any of theembodiments, variations, and/or individual compounds specified orclaimed herein, both possible chiral centers are intended to beencompassed unless it is specifically specified otherwise.

A. Salts, Hydrates, and Prodrugs of DPP-IV Inhibitors

It should be recognized that the compounds of the present invention maybe present and optionally administered in the form of salts, hydratesand prodrugs that are converted in vivo into the compounds of thepresent invention. For example, it is within the scope of the presentinvention to convert the compounds of the present invention into and usethem in the form of their pharmaceutically acceptable salts derived fromvarious organic and inorganic acids and bases in accordance withprocedures well known in the art.

When the compounds of the present invention possess a free base form,the compounds can be prepared as a pharmaceutically acceptable acidaddition salt by reacting the free base form of the compound with apharmaceutically acceptable inorganic or organic acid, e.g.,hydrohalides such as hydrochloride, hydrobromide, hydroiodide; othermineral acids and their corresponding salts such as sulfate, nitrate,phosphate, etc.; and alkyl and monoarylsulfonates such asethanesulfonate, toluenesulfonate and benzenesulfonate; and otherorganic acids and their corresponding salts such as acetate, tartrate,maleate, succinate, citrate, benzoate, salicylate and ascorbate. Furtheracid addition salts of the present invention include, but are notlimited to: adipate, alginate, arginate, aspartate, bisulfate,bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate,chloride, chlorobenzoate, cyclopentanepropionate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate,galacterate (from mucic acid), galacturonate, glucoheptaoate, gluconate,glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate,hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate,lactobionate, malate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate and phthalate. It should be recognized that the free baseforms will typically differ from their respective salt forms somewhat inphysical properties such as solubility in polar solvents, but otherwisethe salts are equivalent to their respective free base forms for thepurposes of the present invention.

When the compounds of the present invention possess a free acid form, apharmaceutically acceptable base addition salt can be prepared byreacting the free acid form of the compound with a pharmaceuticallyacceptable inorganic or organic base. Examples of such bases are alkalimetal hydroxides including potassium, sodium and lithium hydroxides;alkaline earth metal hydroxides such as barium and calcium hydroxides;alkali metal alkoxides, e.g. potassium ethanolate and sodiumpropanolate; and various organic bases such as ammonium hydroxide,piperidine, diethanolamine and N-methylglutamine. Also included are thealuminum salts of the compounds of the present invention. Further basesalts of the present invention include, but are not limited to: copper,ferric, ferrous, lithium, magnesium, manganic, manganous, potassium,sodium and zinc salts. Organic base salts include, but are not limitedto, salts of primary, secondary and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, e.g., arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, iso-propylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris-(hydroxymethyl)-methylamine(tromethamine). It should be recognized that the free acid forms willtypically differ from their respective salt forms somewhat in physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free acid forms for the purposes ofthe present invention.

Compounds of the present invention that comprise basicnitrogen-containing groups may be quaternized with such agents as(C₁₋₄)alkyl halides, e.g., methyl, ethyl, iso-propyl and tert-butylchlorides, bromides and iodides; di(C₁₋₄)alkyl sulfates, e.g., dimethyl,diethyl and diamyl sulfates; (C₁₀₋₁₈)alkyl halides, e.g., decyl,dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides;and aryl (C₁₋₄)alkyl halides, e.g., benzyl chloride and phenethylbromide. Such salts permit the preparation of both water-soluble andoil-soluble compounds of the present invention.

N-oxides of compounds according to the present invention can be preparedby methods known to those of ordinary skill in the art. For example,N-oxides can be prepared by treating an unoxidized form of the compoundwith an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid,perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or thelike) in a suitable inert organic solvent (e.g., a halogenatedhydrocarbon such as dichloromethane) at approximately 0° C.Alternatively, the N-oxides of the compounds can be prepared from theN-oxide of an appropriate starting material.

Prodrug derivatives of compounds according to the present invention canbe prepared by modifying substituents of compounds of the presentinvention that are then converted in vivo to a different substituent. Itis noted that in many instances, the prodrugs themselves also fallwithin the scope of the range of compounds according to the presentinvention. For example, prodrugs can be prepared by reacting a compoundwith a carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate,para-nitrophenyl carbonate, or the like) or an acylating agent. Furtherexamples of methods of making prodrugs are described in Saulnier et al.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985.

Protected derivatives of compounds of the present invention can also bemade. Examples of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, Protecting Groupsin Organic Synthesis, 3^(rd) edition, John Wiley & Sons, Inc. 1999.

Compounds of the present invention may also be conveniently prepared, orformed during the process of the invention, as solvates (e.g. hydrates).Hydrates of compounds of the present invention may be convenientlyprepared by recrystallization from an aqueous/organic solvent mixture,using organic solvents such as dioxin, tetrahydrofuran or methanol.

A “pharmaceutically acceptable salt”, as used herein, is intended toencompass any compound according to the present invention that isutilized in the form of a salt thereof, especially where the saltconfers on the compound improved pharmacokinetic properties as comparedto the free form of compound or a different salt form of the compound.The pharmaceutically acceptable salt form may also initially conferdesirable pharmacokinetic properties on the compound that it did notpreviously possess, and may even positively affect the pharmacodynamicsof the compound with respect to its therapeutic activity in the body. Anexample of a pharmacokinetic property that may be favorably affected isthe manner in which the compound is transported across cell membranes,which in turn may directly and positively affect the absorption,distribution, biotransformation and excretion of the compound. While theroute of administration of the pharmaceutical composition is important,and various anatomical, physiological and pathological factors cancritically affect bioavailability, the solubility of the compound isusually dependent upon the character of the particular salt formthereof, which it utilized. One of skill in the art will appreciate thatan aqueous solution of the compound will provide the most rapidabsorption of the compound into the body of a subject being treated,while lipid solutions and suspensions, as well as solid dosage forms,will result in less rapid adsorption of the compound.

3. Indications for Use of DPP-IV Inhibitors

DPP-IV is believed to contribute to the pathology and/or symptomology ofseveral different diseases such that reduction of the activity of DPP-IVin a subject through inhibition may be used to therapeutically addressthese disease states. Examples of various diseases that may be treatedusing the DPP-IV inhibitors of the present invention are describedherein. It is noted that additional diseases beyond those disclosedherein may be later identified as the biological roles that DPP-IV playsin various pathways becomes more fully understood.

One set of indications that DPP-IV inhibitors of the present inventionmay be used to treat are those involving the prevention and treatment ofdiabetes and obesity, in particular type 2 diabetes mellitus, diabeticdislipidemia, conditions of impaired glucose tolerance (IGT), conditionsof impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis,appetite regulation and obesity.

DPP-IV inhibitors of the present invention may also be used asimmunosuppressants (or cytokine release suppressant drugs) for thetreatment of among other things: organ transplant rejection; autoimmunediseases such as inflammatory bowel disease, multiple sclerosis andrheumatoid arthritis; and the treatment of AIDS.

DPP-IV inhibitors of the present invention may also be used for treatingvarious cancers including breast cancer, lung cancer and prostatecancer.

DPP-IV inhibitors of the present invention may also be used to treatdermatological diseases such as psoriasis, rheumatoid arthritis (RA) andlichen planus.

DPP-IV inhibitors of the present invention may also be used to treatinfertility and amenorrhea.

DPP-IV inhibitors of the present invention may also be used to modulatecleavage of various cytokines (stimulating hematopoietic cells), growthfactors and neuropeptides. For example, such conditions occur frequentlyin patients who are immunosuppressed, for example, as a consequence ofchemotherapy and/or radiation therapy for cancer.

DPP-IV inhibitors of the present invention may also be used prevent orreduce cleavage of N-terminal Tyr-Ala from growth hormone-releasingfactor. Accordingly, these inhibitors may be used in the treatment ofshort stature due to growth hormone deficiency (Dwarfism) and forpromoting GH-dependent tissue growth or re-growth.

DPP-IV inhibitors of the present invention may also be used to addressdisease states associated with cleavage of neuropeptides and thus may beuseful for the regulation or normalization of neurological disorders.

For oncology indications, DPP-IV inhibitors of the present invention maybe used in conjunction with other agents to inhibit undesirable anduncontrolled cell proliferation. Examples of other anti-cellproliferation agents that may be used in conjunction with the DPP-IVinhibitors of the present invention include, but are not limited to,retinoid acid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN™protein, ENDOSTATIN™ protein, suramin, squalamine, tissue inhibitor ofmetalloproteinase-1, tissue inhibitor of metalloproteinase-2,plasminogen activator inhibitor-1, plasminogen activator inhibitor-2,cartilage-derived inhibitor, paclitaxel, platelet factor 4, protaminesulfate (clupeine), sulfated chitin derivatives (prepared from queencrab shells), sulfated polysaccharide peptidoglycan complex (sp-pg),staurosporine, modulators of matrix metabolism, including for example,proline analogs ((l-azetidine-2-carboxylic acid (LACA)),cishydroxyproline, d,l-3,4-dehydroproline, thiaproline,beta.-aminopropionitrile fumarate,4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone, methotrexate, mitoxantrone,heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin,beta.-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodiumthiomalate, d-penicillamine (CDPT), beta.-1-anticollagenase-serum,alpha.2-antiplasmin, bisantrene, lobenzarit disodium,n-2-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”,thalidomide; angostatic steroid, carboxyaminoimidazole;metalloproteinase inhibitors such as BB94. Other anti-angiogenesisagents that may be used include antibodies, preferably monoclonalantibodies against these angiogenic growth factors: bFGF, aFGF, FGF-5,VEGF isoforms, VEGF-C, HGF/SF and Ang-1/Ang-2. Ferrara N. and Alitalo,K. “Clinical application of angiogenic growth factors and theirinhibitors” (1999) Nature Medicine 5:1359-1364.

4. Compositions Comprising DPP-IV Inhibitors

A wide variety of compositions and administration methods may be used inconjunction with the DPP-IV inhibitors of the present invention. Suchcompositions may include, in addition to the DPP-IV inhibitors of thepresent invention, conventional pharmaceutical excipients, and otherconventional, pharmaceutically inactive agents. Additionally, thecompositions may include active agents in addition to the DPP-IVinhibitors of the present invention. These additional active agents mayinclude additional compounds according to the invention, and/or one ormore other pharmaceutically active agents.

The compositions may be in gaseous, liquid, semi-liquid or solid form,formulated in a manner suitable for the route of administration to beused. For oral administration, capsules and tablets are typically used.For parenteral administration, reconstitution of a lyophilized powder,prepared as described herein, is typically used.

Compositions comprising DPP-IV inhibitors of the present invention maybe administered or coadministered orally, parenterally,intraperitoneally, intravenously, intraarterially, transdermally,sublingually, intramuscularly, rectally, transbuccally, intranasally,liposomally, via inhalation, vaginally, intraoccularly, via localdelivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, or intrathecally. The compoundsand/or compositions according to the invention may also be administeredor coadministered in slow release dosage forms.

The DPP-IV inhibitors and compositions comprising them may beadministered or coadministered in any conventional dosage form.Co-administration in the context of this invention is intended to meanthe administration of more than one therapeutic agent, one of whichincludes a DPP-IV inhibitor, in the course of a coordinated treatment toachieve an improved clinical outcome. Such co-administration may also becoextensive, that is, occurring during overlapping periods of time.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application may optionally include one or more of thefollowing components: a sterile diluent, such as water for injection,saline solution, fixed oil, polyethylene glycol, glycerine, propyleneglycol or other synthetic solvent; antimicrobial agents, such as benzylalcohol and methyl parabens; antioxidants, such as ascorbic acid andsodium bisulfite; chelating agents, such as ethylenediaminetetraaceticacid (EDTA); buffers, such as acetates, citrates and phosphates; agentsfor the adjustment of tonicity such as sodium chloride or dextrose, andagents for adjusting the acidity or alkalinity of the composition, suchas alkaline or acidifying agents or buffers like carbonates,bicarbonates, phosphates, hydrochloric acid, and organic acids likeacetic and citric acid. Parenteral preparations may optionally beenclosed in ampules, disposable syringes or single or multiple dosevials made of glass, plastic or other suitable material.

When DPP-IV inhibitors according to the present invention exhibitinsufficient solubility, methods for solubilizing the compounds may beused. Such methods are known to those of skill in this art, and include,but are not limited to, using cosolvents, such as dimethylsulfoxide(DMSO), using surfactants, such as TWEEN, or dissolution in aqueoussodium bicarbonate. Derivatives of the compounds, such as prodrugs ofthe compounds may also be used in formulating effective pharmaceuticalcompositions.

Upon mixing or adding DPP-IV inhibitors according to the presentinvention to a composition, a solution, suspension, emulsion or the likemay be formed. The form of the resulting composition will depend upon anumber of factors, including the intended mode of administration, andthe solubility of the compound in the selected carrier or vehicle. Theeffective concentration needed to ameliorate the disease being treatedmay be empirically determined.

Compositions according to the present invention are optionally providedfor administration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, dry powders for inhalers, granules,sterile parenteral solutions or suspensions, and oral solutions orsuspensions, and oil-water emulsions containing suitable quantities ofthe compounds, particularly the pharmaceutically acceptable salts,preferably the sodium salts, thereof. The pharmaceuticallytherapeutically active compounds and derivatives thereof are typicallyformulated and administered in unit-dosage forms or multiple-dosageforms. Unit-dose forms, as used herein, refers to physically discreteunits suitable for human and animal subjects and packaged individuallyas is known in the art. Each unit-dose contains a predetermined quantityof the therapeutically active compound sufficient to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier, vehicle or diluent. Examples of unit-dose forms includeampoules and syringes individually packaged tablet or capsule. Unit-doseforms may be administered in fractions or multiples thereof. Amultiple-dose form is a plurality of identical unit-dosage formspackaged in a single container to be administered in segregatedunit-dose form. Examples of multiple-dose forms include vials, bottlesof tablets or capsules or bottles of pint or gallons. Hence, multipledose form is a multiple of unit-doses that are not segregated inpackaging.

In addition to one or more DPP-IV inhibitors according to the presentinvention, the composition may comprise: a diluent such as lactose,sucrose, dicalcium phosphate, or carboxymethylcellulose; a lubricant,such as magnesium stearate, calcium stearate and talc; and a binder suchas starch, natural gums, such as gum acaciagelatin, glucose, molasses,polyinylpyrrolidine, celluloses and derivatives thereof, povidone,crospovidones and other such binders known to those of skill in the art.Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, or otherwise mixing an activecompound as defined above and optional pharmaceutical adjuvants in acarrier, such as, for example, water, saline, aqueous dextrose,glycerol, glycols, ethanol, and the like, to form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of auxiliary substances suchas wetting agents, emulsifying agents, or solubilizing agents, pHbuffering agents and the like, for example, acetate, sodium citrate,cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodiumacetate, triethanolamine oleate, and other such agents. Actual methodsof preparing such dosage forms are known in the art, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15thEdition, 1975. The composition or formulation to be administered will,in any event, contain a sufficient quantity of a DPP-IV inhibitor of thepresent invention to reduce DPP-IV activity in vivo, thereby treatingthe disease state of the subject.

Dosage forms or compositions may optionally comprise one or more DPP-IVinhibitors according to the present invention in the range of 0.005% to100% (weight/weight) with the balance comprising additional substancessuch as those described herein. For oral administration, apharmaceutically acceptable composition may optionally comprise any oneor more commonly employed excipients, such as, for examplepharmaceutical grades of mannitol, lactose, starch, magnesium stearate,talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose,magnesium carbonate, sodium saccharin, talcum. Such compositions includesolutions, suspensions, tablets, capsules, powders, dry powders forinhalers and sustained release formulations, such as, but not limitedto, implants and microencapsulated delivery systems, and biodegradable,biocompatible polymers, such as collagen, ethylene vinyl acetate,polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid andothers. Methods for preparing these formulations are known to thoseskilled in the art. The compositions may optionally contain 0.01%-100%(weight/weight) of one or more DPP-IV inhibitors, optionally 0.1-95%,and optionally 1-95%.

Salts, preferably sodium salts, of the DPP-IV inhibitors may be preparedwith carriers that protect the compound against rapid elimination fromthe body, such as time release formulations or coatings. Theformulations may further include other active compounds to obtaindesired combinations of properties.

A. Formulations for Oral Administration

Oral pharmaceutical dosage forms may be as a solid, gel or liquid.Examples of solid dosage forms include, but are not limited to tablets,capsules, granules, and bulk powders. More specific examples of oraltablets include compressed, chewable lozenges and tablets that may beenteric-coated, sugar-coated or film-coated. Examples of capsulesinclude hard or soft gelatin capsules. Granules and powders may beprovided in non-effervescent or effervescent forms. Each may be combinedwith other ingredients known to those skilled in the art.

In certain embodiments, DPP-IV inhibitors according to the presentinvention are provided as solid dosage forms, preferably capsules ortablets. The tablets, pills, capsules, troches and the like mayoptionally contain one or more of the following ingredients, orcompounds of a similar nature: a binder; a diluent; a disintegratingagent; a lubricant; a glidant; a sweetening agent; and a flavoringagent.

Examples of binders that may be used include, but are not limited to,microcrystalline cellulose, gum tragacanth, glucose solution, acaciamucilage, gelatin solution, sucrose and starch paste.

Examples of lubricants that may be used include, but are not limited to,talc, starch, magnesium or calcium stearate, lycopodium and stearicacid.

Examples of diluents that may be used include, but are not limited to,lactose, sucrose, starch, kaolin, salt, mannitol and dicalciumphosphate.

Examples of glidants that may be used include, but are not limited to,colloidal silicon dioxide.

Examples of disintegrating agents that may be used include, but are notlimited to, crosscarmellose sodium, sodium starch glycolate, alginicacid, corn starch, potato starch, bentonite, methylcellulose, agar andcarboxymethylcellulose.

Examples of coloring agents that may be used include, but are notlimited to, any of the approved certified water soluble FD and C dyes,mixtures thereof, and water insoluble FD and C dyes suspended on aluminahydrate.

Examples of sweetening agents that may be used include, but are notlimited to, sucrose, lactose, mannitol and artificial sweetening agentssuch as sodium cyclamate and saccharin, and any number of spray-driedflavors.

Examples of flavoring agents that may be used include, but are notlimited to, natural flavors extracted from plants such as fruits andsynthetic blends of compounds that produce a pleasant sensation, suchas, but not limited to peppermint and methyl salicylate.

Examples of wetting agents that may be used include, but are not limitedto, propylene glycol monostearate, sorbitan monooleate, diethyleneglycol monolaurate and polyoxyethylene lauryl ether.

Examples of anti-emetic coatings that may be used include, but are notlimited to, fatty acids, fats, waxes, shellac, ammoniated shellac andcellulose acetate phthalates.

Examples of film coatings that may be used include, but are not limitedto, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the salt of the compound mayoptionally be provided in a composition that protects it from the acidicenvironment of the stomach. For example, the composition can beformulated in an enteric coating that maintains its integrity in thestomach and releases the active compound in the intestine. Thecomposition may also be formulated in combination with an antacid orother such ingredient.

When the dosage unit form is a capsule, it may optionally additionallycomprise a liquid carrier such as a fatty oil. In addition, dosage unitforms may optionally additionally comprise various other materials thatmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents.

Compounds according to the present invention may also be administered asa component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may optionally comprise, in addition to theactive compounds, sucrose as a sweetening agent and certainpreservatives, dyes and colorings and flavors.

The DPP-IV inhibitors of the present invention may also be mixed withother active materials that do not impair the desired action, or withmaterials that supplement the desired action, such as antacids, H2blockers, and diuretics. For example, if a compound is used for treatingasthma or hypertension, it may be used with other bronchodilators andantihypertensive agents, respectively.

Examples of pharmaceutically acceptable carriers that may be included intablets comprising DPP-IV inhibitors of the present invention include,but are not limited to binders, lubricants, diluents, disintegratingagents, coloring agents, flavoring agents, and wetting agents.Enteric-coated tablets, because of the enteric-coating, resist theaction of stomach acid and dissolve or disintegrate in the neutral oralkaline intestines. Sugar-coated tablets may be compressed tablets towhich different layers of pharmaceutically acceptable substances areapplied. Film-coated tablets may be compressed tablets that have beencoated with polymers or other suitable coating. Multiple compressedtablets may be compressed tablets made by more than one compressioncycle utilizing the pharmaceutically acceptable substances previouslymentioned. Coloring agents may also be used in tablets. Flavoring andsweetening agents may be used in tablets, and are especially useful inthe formation of chewable tablets and lozenges.

Examples of liquid oral dosage forms that may be used include, but arenot limited to, aqueous solutions, emulsions, suspensions, solutionsand/or suspensions reconstituted from non-effervescent granules andeffervescent preparations reconstituted from effervescent granules.

Examples of aqueous solutions that may be used include, but are notlimited to, elixirs and syrups. As used herein, elixirs refer to clear,sweetened, hydroalcoholic preparations. Examples of pharmaceuticallyacceptable carriers that may be used in elixirs include, but are notlimited to solvents. Particular examples of solvents that may be usedinclude glycerin, sorbitol, ethyl alcohol and syrup. As used herein,syrups refer to concentrated aqueous solutions of a sugar, for example,sucrose. Syrups may optionally further comprise a preservative.

Emulsions refer to two-phase systems in which one liquid is dispersed inthe form of small globules throughout another liquid. Emulsions mayoptionally be oil-in-water or water-in-oil emulsions. Examples ofpharmaceutically acceptable carriers that may be used in emulsionsinclude, but are not limited to non-aqueous liquids, emulsifying agentsand preservatives.

Examples of pharmaceutically acceptable substances that may be used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents.

Examples of pharmaceutically acceptable substances that may be used ineffervescent granules, to be reconstituted into a liquid oral dosageform, include organic adds and a source of carbon dioxide.

Coloring and flavoring agents may optionally be used in all of the abovedosage forms.

Particular examples of preservatives that may be used include glycerin,methyl and propylparaben, benzoic add, sodium benzoate and alcohol.

Particular examples of non-aqueous liquids that may be used in emulsionsinclude mineral oil and cottonseed oil.

Particular examples of emulsifying agents that may be used includegelatin, acacia, tragacanth, bentonite, and surfactants such aspolyoxyethylene sorbitan monooleate.

Particular examples of suspending agents that may be used include sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluentsinclude lactose and sucrose. Sweetening agents include sucrose, syrups,glycerin and artificial sweetening agents such as sodium cyclamate andsaccharin.

Particular examples of wetting agents that may be used include propyleneglycol monostearate, sorbitan monooleate, diethylene glycol monolaurateand polyoxyethylene lauryl ether.

Particular examples of organic acids that may be used include citric andtartaric acid.

Sources of carbon dioxide that may be used in effervescent compositionsinclude sodium bicarbonate and sodium carbonate. Coloring agents includeany of the approved certified water soluble FD and C dyes, and mixturesthereof.

Particular examples of flavoring agents that may be used include naturalflavors extracted from plants such fruits, and synthetic blends ofcompounds that produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is preferablyencapsulated in a gelatin capsule. Such solutions, and the preparationand encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245;4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g.,for example, in a polyethylene glycol, may be diluted with a sufficientquantity of a pharmaceutically acceptable liquid carrier, e.g. water, tobe easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g. propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. Re 28,819 and4,358,603.

B. Injectables, Solutions and Emulsions

The present invention is also directed to compositions designed toadminister the DPP-IV inhibitors of the present invention by parenteraladministration, generally characterized by injection, eithersubcutaneously, intramuscularly or intravenously. Injectables may beprepared in any conventional form, for example as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions.

Examples of excipients that may be used in conjunction with injectablesaccording to the present invention include, but are not limited towater, saline, dextrose, glycerol or ethanol. The injectablecompositions may also optionally comprise minor amounts of non-toxicauxiliary substances such as wetting or emulsifying agents, pH bufferingagents, stabilizers, solubility enhancers, and other such agents, suchas for example, sodium acetate, sorbitan monolaurate, triethanolamineoleate and cyclodextrins. Implantation of a slow-release orsustained-release system, such that a constant level of dosage ismaintained (see, e.g., U.S. Pat. No. 3,710,795) is also contemplatedherein. The percentage of active compound contained in such parenteralcompositions is highly dependent on the specific nature thereof, as wellas the activity of the compound and the needs of the subject.

Parenteral administration of the formulations includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as the lyophilized powders describedherein, ready to be combined with a solvent just prior to use, includinghypodermic tablets, sterile suspensions ready for injection, sterile dryinsoluble products ready to be combined with a vehicle just prior to useand sterile emulsions. The solutions may be either aqueous ornonaqueous.

When administered intravenously, examples of suitable carriers include,but are not limited to physiological saline or phosphate buffered saline(PBS), and solutions containing thickening and solubilizing agents, suchas glucose, polyethylene glycol, and polypropylene glycol and mixturesthereof.

Examples of pharmaceutically acceptable carriers that may optionally beused in parenteral preparations include, but are not limited to aqueousvehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents,buffers, antioxidants, local anesthetics, suspending and dispersingagents, emulsifying agents, sequestering or chelating agents and otherpharmaceutically acceptable substances.

Examples of aqueous vehicles that may optionally be used include SodiumChloride Injection, Ringers Injection, Isotonic Dextrose Injection,Sterile Water Injection, Dextrose and Lactated Ringers Injection.

Examples of nonaqueous parenteral vehicles that may optionally be usedinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil.

Antimicrobial agents in bacteriostatic or fungistatic concentrations maybe added to parenteral preparations, particularly when the preparationsare packaged in multiple-dose containers and thus designed to be storedand multiple aliquots to be removed. Examples of antimicrobial agentsthat may used include phenols or cresols, mercurials, benzyl alcohol,chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters,thimerosal, benzalkonium chloride and benzethonium chloride.

Examples of isotonic agents that may be used include sodium chloride anddextrose. Examples of buffers that may be used include phosphate andcitrate. Examples of antioxidants that may be used include sodiumbisulfate. Examples of local anesthetics that may be used includeprocaine hydrochloride. Examples of suspending and dispersing agentsthat may be used include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Examples of emulsifying agentsthat may be used include Polysorbate 80 (TWEEN 80). A sequestering orchelating agent of metal ions include EDTA.

Pharmaceutical carriers may also optionally include ethyl alcohol,polyethylene glycol and propylene glycol for water miscible vehicles andsodium hydroxide, hydrochloric acid, citric acid or lactic acid for pHadjustment.

The concentration of a DPP-IV inhibitor in the parenteral formulationmay be adjusted so that an injection administers a pharmaceuticallyeffective amount sufficient to produce the desired pharmacologicaleffect. The exact concentration of a DPP-IV inhibitor and/or dosage tobe used will ultimately depend on the age, weight and condition of thepatient or animal as is known in the art.

Unit-dose parenteral preparations may be packaged in an ampoule, a vialor a syringe with a needle. All preparations for parenteraladministration should be sterile, as is know and practiced in the art.

Injectables may be designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,preferably more than 1% w/w of the DPP-IV inhibitor to the treatedtissue(s). The DPP-IV inhibitor may be administered at once, or may bedivided into a number of smaller doses to be administered at intervalsof time. It is understood that the precise dosage and duration oftreatment will be a function of the location of where the composition isparenterally administered, the carrier and other variables that may bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values may also vary with the age of theindividual treated. It is to be further understood that for anyparticular subject, specific dosage regimens may need to be adjustedover time according to the individual need and the professional judgmentof the person administering or supervising the administration of theformulations. Hence, the concentration ranges set forth herein areintended to be exemplary and are not intended to limit the scope orpractice of the claimed formulations.

The DPP-IV inhibitor may optionally be suspended in micronized or othersuitable form or may be derivatized to produce a more soluble activeproduct or to produce a prodrug. The form of the resulting mixturedepends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the disease state and may be empiricallydetermined.

C. Lyophilized Powders

The DPP-IV inhibitors of the present invention may also be prepared aslyophilized powders, which can be reconstituted for administration assolutions, emulsions and other mixtures. The lyophilized powders mayalso be formulated as solids or gels.

Sterile, lyophilized powder may be prepared by dissolving the compoundin a sodium phosphate buffer solution containing dextrose or othersuitable excipient. Subsequent sterile filtration of the solutionfollowed by lyophilization under standard conditions known to those ofskill in the art provides the desired formulation. Briefly, thelyophilized powder may optionally be prepared by dissolving dextrose,sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose orother suitable agent, about 1-20%, preferably about 5 to 15%, in asuitable buffer, such as citrate, sodium or potassium phosphate or othersuch buffer known to those of skill in the art at, typically, aboutneutral pH. Then, a DPP-IV inhibitor is added to the resulting mixture,preferably above room temperature, more preferably at about 30-35° C.,and stirred until it dissolves. The resulting mixture is diluted byadding more buffer to a desired concentration. The resulting mixture issterile filtered or treated to remove particulates and to insuresterility, and apportioned into vials for lyophilization. Each vial maycontain a single dosage or multiple dosages of the DPP-IV inhibitor.

D. Topical Administration

The DPP-IV inhibitors of the present invention may also be administeredas topical mixtures. Topical mixtures may be used for local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The DPP-IV inhibitors may be formulated as aerosols for topicalapplication, such as by inhalation (see, U.S. Pat. Nos. 4,044,126,4,414,209, and 4,364,923, which describe aerosols for delivery of asteroid useful for treatment inflammatory diseases, particularlyasthma). These formulations for administration to the respiratory tractcan be in the form of an aerosol or solution for a nebulizer, or as amicrofine powder for insufflation, alone or in combination with an inertcarrier such as lactose. In such a case, the particles of theformulation will typically have diameters of less than 50 microns,preferably less than 10 microns.

The DPP-IV inhibitors may also be formulated for local or topicalapplication, such as for topical application to the skin and mucousmembranes, such as in the eye, in the form of gels, creams, and lotionsand for application to the eye or for intracisternal or intraspinalapplication. Topical administration is contemplated for transdermaldelivery and also for administration to the eyes or mucosa, or forinhalation therapies. Nasal solutions of the DPP-IV inhibitor alone orin combination with other pharmaceutically acceptable excipients canalso be administered.

E. Formulations for Other Routes of Administration

Depending upon the disease state being treated, other routes ofadministration, such as topical application, transdermal patches, andrectal administration, may also be used. For example, pharmaceuticaldosage forms for rectal administration are rectal suppositories,capsules and tablets for systemic effect. Rectal suppositories are usedherein mean solid bodies for insertion into the rectum that melt orsoften at body temperature releasing one or more pharmacologically ortherapeutically active ingredients. Pharmaceutically acceptablesubstances utilized in rectal suppositories are bases or vehicles andagents to raise the melting point. Examples of bases include cocoabutter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethyleneglycol) and appropriate mixtures of mono-, di- and triglycerides offatty acids. Combinations of the various bases may be used. Agents toraise the melting point of suppositories include spermaceti and wax.Rectal suppositories may be prepared either by the compressed method orby molding. The typical weight of a rectal suppository is about 2 to 3gm. Tablets and capsules for rectal administration may be manufacturedusing the same pharmaceutically acceptable substance and by the samemethods as for formulations for oral administration.

F. Examples of Formulations

The following are particular examples of oral, intravenous and tabletformulations that may optionally be used with compounds of the presentinvention. It is noted that these formulations may be varied dependingon the particular compound being used and the indication for which theformulation is going to be used. ORAL FORMULATION Compound of thePresent Invention 10-100 mg Citric Acid Monohydrate 105 mg SodiumHydroxide 18 mg Flavoring Water q.s. to 100 mL

INTRAVENOUS FORMULATION Compound of the Present Invention 0.1-10 mgDextrose Monohydrate q.s. to make isotonic Citric Acid Monohydrate 1.05mg Sodium Hydroxide 0.18 mg Water for Injection q.s. to 1.0 mL

TABLET FORMULATION Compound of the Present Invention  1%Microcrystalline Cellulose 73% Stearic Acid 25% Colloidal Silica  1%.5. Kits Comprising DPP-IV Inhibitors

The invention is also directed to kits and other articles of manufacturefor treating diseases associated with DPP-IV. It is noted that diseasesare intended to cover all conditions for which the DPP-IV possessesactivity that contributes to the pathology and/or symptomology of thecondition.

In one embodiment, a kit is provided that comprises a compositioncomprising at least one DPP-IV inhibitor of the present invention incombination with instructions. The instructions may indicate the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also comprise packagingmaterials. The packaging material may comprise a container for housingthe composition. The kit may also optionally comprise additionalcomponents, such as syringes for administration of the composition. Thekit may comprise the composition in single or multiple dose forms.

In another embodiment, an article of manufacture is provided thatcomprises a composition comprising at least one DPP-IV inhibitor of thepresent invention in combination with packaging materials. The packagingmaterial may comprise a container for housing the composition. Thecontainer may optionally comprise a label indicating the disease statefor which the composition is to be administered, storage information,dosing information and/or instructions regarding how to administer thecomposition. The kit may also optionally comprise additional components,such as syringes for administration of the composition. The kit maycomprise the composition in single or multiple dose forms.

It is noted that the packaging material used in kits and articles ofmanufacture according to the present invention may form a plurality ofdivided containers such as a divided bottle or a divided foil packet.The container can be in any conventional shape or form as known in theart which is made of a pharmaceutically acceptable material, for examplea paper or cardboard box, a glass or plastic bottle or jar, are-sealable bag (for example, to hold a “refill” of tablets forplacement into a different container), or a blister pack with individualdoses for pressing out of the pack according to a therapeutic schedule.The container that is employed will depend on the exact dosage forminvolved, for example a conventional cardboard box would not generallybe used to hold a liquid suspension. It is feasible that more than onecontainer can be used together in a single package to market a singledosage form. For example, tablets may be contained in a bottle that isin turn contained within a box. Typically the kit includes directionsfor the administration of the separate components. The kit form isparticularly advantageous when the separate components are preferablyadministered in different dosage forms (e.g., oral, topical, transdermaland parenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician.

One particular example of a kit according to the present invention is aso-called blister pack. Blister packs are well known in the packagingindustry and are being widely used for the packaging of pharmaceuticalunit dosage forms (tablets, capsules, and the like). Blister packsgenerally consist of a sheet of relatively stiff material covered with afoil of a preferably transparent plastic material. During the packagingprocess recesses are formed in the plastic foil. The recesses have thesize and shape of individual tablets or capsules to be packed or mayhave the size and shape to accommodate multiple tablets and/or capsulesto be packed. Next, the tablets or capsules are placed in the recessesaccordingly and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are individually sealed or collectively sealed, as desired, inthe recesses between the plastic foil and the sheet. Preferably thestrength of the sheet is such that the tablets or capsules can beremoved from the blister pack by manually applying pressure on therecesses whereby an opening is formed in the sheet at the place of therecess. The tablet or capsule can then be removed via said opening.

Another specific embodiment of a kit is a dispenser designed to dispensethe daily doses one at a time in the order of their intended use.Preferably, the dispenser is equipped with a memory-aid, so as tofurther facilitate compliance with the regimen. An example of such amemory-aid is a mechanical counter that indicates the number of dailydoses that has been dispensed. Another example of such a memory-aid is abattery-powered micro-chip memory coupled with a liquid crystal readout,or audible reminder signal which, for example, reads out the date thatthe last daily dose has been taken and/or reminds one when the next doseis to be taken.

EXAMPLES 1. Preparation of DPP-IV Inhibitors

Various methods may be developed for synthesizing compounds according tothe present invention. Representative methods for synthesizing thesecompounds are provided in the Examples. It is noted, however, that thecompounds of the present invention may also be synthesized by othersynthetic routes that others may devise.

It will be readily recognized that certain compounds according to thepresent invention have atoms with linkages to other atoms that confer aparticular stereochemistry to the compound (e.g., chiral centers). It isrecognized that synthesis of compounds according to the presentinvention may result in the creation of mixtures of differentstereoisomers (enantiomers, diastereomers). Unless a particularstereochemistry is specified, recitation of a compound is intended toencompass all of the different possible stereoisomers.

Various methods for separating mixtures of different stereoisomers areknown in the art. For example, a racemic mixture of a compound may bereacted with an optically active resolving agent to form a pair ofdiastereoisomeric compounds. The diastereomers may then be separated inorder to recover the optically pure enantiomers. Dissociable complexesmay also be used to resolve enantiomers (e.g., crystallinediastereoisomeric salts). Diastereomers typically have sufficientlydistinct physical properties (e.g., melting points, boiling points,solubilities, reactivity, etc.) that they can be readily separated bytaking advantage of these dissimilarities. For example, diastereomerscan typically be separated by chromatography or by separation/resolutiontechniques based upon differences in solubility. A more detaileddescription of techniques that can be used to resolve stereoisomers ofcompounds from their racemic mixture can be found in Jean Jacques AndreCollet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, JohnWiley & Sons, Inc. (1981).

Compounds according to the present invention can also be prepared as apharmaceutically acceptable acid addition salt by reacting the free baseform of the compound with a pharmaceutically acceptable inorganic ororganic acid. Alternatively, a pharmaceutically acceptable base additionsalt of a compound can be prepared by reacting the free acid form of thecompound with a pharmaceutically acceptable inorganic or organic base.Inorganic and organic acids and bases suitable for the preparation ofthe pharmaceutically acceptable salts of compounds are set forth in thedefinitions section of this application. Alternatively, the salt formsof the compounds can be prepared using salts of the starting materialsor intermediates.

The free acid or free base forms of the compounds can be prepared fromthe corresponding base addition salt or acid addition salt form. Forexample, a compound in an acid addition salt form can be converted tothe corresponding free base by treating with a suitable base (e.g.,ammonium hydroxide solution, sodium hydroxide, and the like). A compoundin a base addition salt form can be converted to the corresponding freeacid by treating with a suitable acid (e.g., hydrochloric acid, etc).

The N-oxides of compounds according to the present invention can beprepared by methods known to those of ordinary skill in the art. Forexample, N-oxides can be prepared by treating an unoxidized form of thecompound with an oxidizing agent (e.g., trifluoroperacetic acid,permaleic acid, perbenzoic acid, peracetic acid,meta-chloroperoxybenzoic acid, or the like) in a suitable inert organicsolvent (e.g., a halogenated hydrocarbon such as dichloromethane) atapproximately 0° C. Alternatively, the N-oxides of the compounds can beprepared from the N-oxide of an appropriate starting material.

Compounds in an unoxidized form can be prepared from N-oxides ofcompounds by treating with a reducing agent (e.g., sulfur, sulfurdioxide, triphenyl phosphine, lithium borohydride, sodium borohydride,phosphorus trichloride, tribromide, or the like) in an suitable inertorganic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or thelike) at 0 to 80° C.

Prodrug derivatives of the compounds can be prepared by methods known tothose of ordinary skill in the art (e.g., for further details seeSaulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p. 1985). For example, appropriate prodrugs can be prepared byreacting a non-derivatized compound with a suitable carbamylating agent(e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, orthe like).

Protected derivatives of the compounds can be made by methods known tothose of ordinary skill in the art. A detailed description of thetechniques applicable to the creation of protecting groups and theirremoval can be found in T. W. Greene, Protecting Groups in OrganicSynthesis, 3^(rd) edition, John Wiley & Sons, Inc. 1999.

Compounds according to the present invention may be convenientlyprepared, or formed during the process of the invention, as solvates(e.g. hydrates). Hydrates of compounds of the present invention may beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds according to the present invention can also be prepared astheir individual stereoisomers by reacting a racemic mixture of thecompound with an optically active resolving agent to form a pair ofdiastereoisomeric compounds, separating the diastereomers and recoveringthe optically pure enantiomer. While resolution of enantiomers can becarried out using covalent diastereomeric derivatives of compounds,dissociable complexes are preferred (e.g., crystalline diastereoisomericsalts). Diastereomers have distinct physical properties (e.g., meltingpoints, boiling points, solubilities, reactivity, etc.) and can bereadily separated by taking advantage of these dissimilarities. Thediastereomers can be separated by chromatography or, preferably, byseparation/resolution techniques based upon differences in solubility.The optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracemization. A more detailed description of the techniques applicableto the resolution of stereoisomers of compounds from their racemicmixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen,Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

g (grams); mg (milligrams);

L (liters); mL (milliliters);

μL (microliters); psi (pounds per square inch);

M (molar); mM (millimolar);

i.v. (intravenous); Hz (Hertz);

MHz (megahertz); mol (moles);

mmol (millimoles); RT (ambient temperature);

min (minutes); h (hours);

mp (melting point); TLC (thin layer chromatography);

Tr (retention time); RP (reverse phase);

MeOH (methanol); i-PrOH (isopropanol);

TEA (triethylamine); TFA (trifluoroacetic acid);

TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran);

DMSO (dimethylsulfoxide); EtOAc (ethyl acetate);

DME (1,2-dimethoxyethane); DCM (dichloromethane);

DCE (dichloroethane); DMF (N,N-dimethylformamide);

DMPU (N,N′-dimethylpropyleneurea); CDI (1,1-carbonyldiimidazole);

IBCF (isobutyl chloroformate); HOAc (acetic acid);

HOSu (N-hydroxysuccinimino); HOBT (1-hydroxybenzotriazole);

Et₂O (diethyl ether); EDCI (ethylcarbodiimino hydrochloride);

BOC (tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl);

DCC (dicyclohexylcarbodiimino); CBZ (benzyloxycarbonyl);

Ac (acetyl); atm (atmosphere);

TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl);

TIPS (triisopropylsilyl); TBS (t-butyldimethylsilyl);

DMAP (4-dimethylaminopyridine); Me (methyl);

OMe (methoxy); Et (ethyl);

Et (ethyl); tBu (tert-butyl);

HPLC (high pressure liquid chromatography);

BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride);

TBAF (tetra-n-butylammonium fluoride);

mCPBA (meta-chloroperbenzoic acid.

All references to ether or Et₂O are to diethyl ether; brine refers to asaturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionsconducted under an inert atmosphere at RT unless otherwise noted.

¹H NMR spectra were recorded on a Bruker Avance 400. Chemical shifts areexpressed in parts per million (ppm). Coupling constants are in units ofhertz (Hz). Splitting patterns describe apparent multiplicities and aredesignated as s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet), br (broad).

Low-resolution mass spectra (MS) and compound purity data were acquiredon a Waters ZQ LC/MS single quadrupole system equipped with electrosprayionization (ESI) source, UV detector (220 and 254 nm), and evaporativelight scattering detector (ELSD). Thin-layer chromatography wasperformed on 0.25 mm E. Merck silica gel plates (60F-254), visualizedwith UV light, 5% ethanolic phosphomolybdic acid, Ninhydrin orp-anisaldehyde solution. Flash column chromatography was performed onsilica gel (230-400 mesh, Merck).

2. Synthetic Schemes for DPP-IV Inhibitors of the Present Invention

DPP-IV inhibitors according to the present invention may be synthesizedaccording to a variety of reaction schemes. Some illustrative schemesare provided herein in the examples. Other reaction schemes could bereadily devised by those skilled in the art.

In the reactions described hereinafter it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice, for examplessee T. W. Greene and P. G. M. Wuts in “Protective Groups in OrganicChemistry” John Wiley and Sons, 1991.

By varying the Q¹ and Q², R₁, R₂, and R₃ groups, a wide variety ofdifferent DPP-IV inhibitors according to the present invention may besynthesized.

In each of the above reaction schemes, the various substituents may beselected from among the various substituents otherwise taught herein.

Descriptions of the syntheses of particular compounds according to thepresent invention based on the above reaction schemes are set forthherein.

3. Examples of DPP-IV Inhibitors

The present invention is further exemplified, but not limited by, thefollowing examples that describe the synthesis of particular compoundsaccording to the invention.

Experimental Methods

2-(6-Chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile(2). To a solution of 6-chlorouracil (20 g, 122 mmol) in a mixture ofDMF-DMSO (6:1, 600 mL) under nitrogen at 0° C., was added sodium hydride(60%, 5.5 g, 137 mmol) in portions. After 0.5 h, lithium bromide (8 g,96 mmol) was added into the mixture and stirred for 15 min at 0° C. Asolution of α-Bromo-o-tolunitrile (25.1 g, 128 mmol) in DMF (30 mL) wasadded dropwise, and stirred at this temperature for 1 h, and then RTovernight. It will be understood that alkylation of the amine may beperformed under standard conditions known in the art, including the useof a base such as NaH, LiH or the like in an organic solvent or mixtureof solvents. The solvent may include DMSO, THF, DMF and the like, ormixtures thereof. In addition, additives may be used, including LiBr,LiI, NaI and the like. The mixture was evaporated and co-evaporated withwater in vacuo to remove most of the DMF, and then poured into ice water(1 L). The precipitate was collected by filtration. The crude productwas suspended in hot AcOEt-CHCl₃ and sonicated for 5 min, allowed tostand at 0° C. for 1 h, and then filtered to give a white solid of thetitle compound (19 g) in 54% yield. It will also be understood by thoseskilled in the art that purification may be accomplished using variousmethods known in the art, including washing with an aqueous/organicsolvent or mixture of solvents, recrystallization and/or columnchromatography. Non-limiting examples of organic solvents and solventmixtures may include ethyl acetate, isopropyl acetate, acetone, THF andthe like. ¹H-NMR (400 MHz, DMSO): δ 11.82 (s, 1H), 7.87 (d, 1H, J=7.6Hz), 7.71 (t, 1H, J=7.6 Hz), 7.51 (t, 1H, J=7.6 Hz), 7.37 (d, H, J=8Hz), 6.06 (s, 1H), 5.31 (s, 2H). MS (ES) [m+H] calc'd for C₁₂H₉ClN₃O₂,262.0; found 262.0.

2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile(3). To a cold (0° C.) solution of benzylated 6-chlorouracil 2 (10 g, 38mmol) in DMF-THF (1:1, 300 mL) under nitrogen, was added NaH (60%, 1.6g, 39.9 mmol) in portions, followed by adding LiBr (2 g). The mixturewas stirred at r.t for 20 min. After adding iodomethane (5.4 mL, 76mmol), the flask was sealed and stirred at this temperature for 10 min,rt for 2 h, and 35° C. overnight, and then concentrated in vacuo. Itwill be understood that alkylation of the amine may be performed understandard conditions known in the art, including the use of a base suchas NaH, LiH or the like in an organic solvent or mixture of solvents.The solvent may include DMSO, THF, DMF and the like, or mixturesthereof. In addition, additives may be used, including LiBr, LiI, NaIand the like. For example, the alkylation can be performed usingmethyliodide and K_(s)CO₃ in acetone. The reaction may be performed atabout 15-45° C., preferably at about 20-43° C., and more preferably atabout 35-41° C. until the reaction is complete. The residue wasdissolved in CHCl₃ and washed with water and brine, dried (Na₂SO₄), andfiltered then concentrated in vacuo. The crude product was crystallizedfrom THF-Hexanes to give 7.6 g (72%) of the title compound 3. It willalso be understood by those skilled in the art that the benzonitrile maybe purified in a variety of organic solvents or solvent mixtures. Forexample, the benzonitrile can be purified by adding a mixture ofdichloromethane and heptane. Optionally, the benzonitrile may be furtherpurified in an organic solvent or mixture of solvents such asdichloromethane, chloroform, acetonitrile, THF, ethyl acetate, isopropylacetate and the like. Preferably, the product is purified and washedwith ethyl acetate. ¹H NMR (400 MHz, DMSO): δ 7.87 (d, 1H, J=7.6 Hz),7.70 (t, 1H, J=7.6 Hz), 7.51 (t, 1H, J=7.6 Hz), 7.40 (d, 1H, J=8 Hz),6.21 (s, 1H), 5.38 (s, 2H), 3.28 (s, 3H). MS (ES) [m+H] calc'd forC₁₃H₁₁ClN₃O₂, 276.1; found 276.1.

2-{6-[3(R)-Amino-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile(4).2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2-H-pyrimidin-1-ylmethyl)-benzonitrile(330 mg, 1.08 mmol), (R)-3-amino-piperidine dihydrochloride (246 mg, 1.4mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were stirred with 200 mgactivated molecular sieves (4 A) in dry MeOH (5 mL) at 100° C. for 2 h.The reaction was filtered through Celite, concentrated in vacuo, andthen diluted with CHCl₃, and washed with water. The water phase wasextracted with CHCl₃ and the combined organic phases were washed withwater, dried (Na₂SO₄), and filtered. TFA (1 mL) was added into thesolution which was then concentrated in vacuo. The residue was dissolvedin a small amount of MeOH, and Et₂O was added to force precipitation.The mixture was allowed to stand at RT overnight. It will be understoodby those skilled in the art that condensation with the amine or aminehydrochloride may be performed in a solvent or mixture of solvents witha base, such as potassium carbonate, sodium bicarbonate and the like, ormixtures thereof. The solvent may comprise both protic and aproticsolvents, or mixtures thereof. For example, the solvent may comprise amixture of isopropyl alcohol and water. Further, the reaction may beheated to about 30-100° C., preferably about 35-55° C., and morepreferably about 45-50° C. until the reaction is complete. Solvents weredecanted, and the solid was washed with Et₂O two times to give 270 mgTFA salt of product 4 as off-white powder. It will also be understoodthat the product may be further purified by washing with an organicsolvent or mixture of solvents. Non-limiting examples of solvent orsolvent mixtures include isopropyl acetate, ethyl acetate,dichloromethane, heptane, and the like. Further, the product mayoptionally be purified by column chromatography. The TFA salt of 4 has¹H-NMR (400 MHz, CDCl₃—CD₃OD 10:1): δ 7.82 (d, 1H, J=7.6 Hz), 7.65 (t,1H, J=7.6 Hz), 7.46 (t, 1H, J=7.6 Hz), 7.23 (d, 1H, J=8.0 Hz), 5.42 (s,1H), 5.50-5.00 (ABq, 2H, J=41.6, 15.2 Hz), 3.30 (m, 2H), 3.16 (s, 3H),2.91 (m, 1H), 2.76 (m, 2H), 1.93 (m, 1H), 1.79 (m, 1H), 1.51 (m, 2H). MS(ES) [m+H] calc'd for C₁₈H₂₂N₅O₂, 340.2; found, 340.2.

The benzonitrile product may be isolated as the free base if desired,but preferably, the product may be further converted to a correspondingacid addition salt. For example, the benzoic acid salt was formed bytreating the benzonitrile product with benzoic acid to form2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-benzonitrilebenzoate (4). Preparation and isolation of the benzoate salt wasperformed by conventional methods for the formation of acid additionsalts. ¹H-NMR (400 MHz, CDCl₃—CD₃OD 10:1): δ 7.82 (d, 1H, J=7.6 Hz),7.65 (t, 1H, J=7.6 Hz), 7.46 (t, 1H, J=7.6 Hz), 7.23 (d, 1H, J=8.0 Hz),5.42 (s, 1H), 5.50-5.00 (ABq, 2H, J=41.6, 15.2 Hz), 3.30 (m, 2H), 3.16(s, 3H), 2.91 (m, 1H), 2.76 (m, 2H), 1.93 (m, 1H), 1.79 (m, 1H), 1.51(m, 2H). MS (ES) [m+H] calc'd for C₁₈H₂₂N₅O₂, 340.2; found, 340.2.

Following the same procedure described above, HCl addition salt wasprepared as follows. A free base form of 4 was isolated after the crudeproduct was washed with water, dried over Na₂SO₄, filtered andconcentrated. The free base product was then dissolved in THF.Alternatively, the free base could be dissolved in other solvents, suchas dioxane, acetonitrile, ethyl acetate, dichloromethane, etc., ormixtures thereof. The solution was then stirred and 1.2 equivalents of4M HCl in dioxane was added dropwise. After 10 min stirring, thesuspended mixture was allowed to stand at rt for 1 h, and then filteredto give the solid HCl salt form of 4. ¹H-NMR (400 MHz, DMSO-D6): δ 7.82(d, 1H, J=7.6 Hz), 7.65 (t, 1H, J=7.6 Hz), 7.46 (t, 1H, J=7.6 Hz), 7.23(d, 1H, J=8.0 Hz), 5.42 (s, 1H), 5.20, 5.08 (ABq, 2H, J=41.6, 15.2 Hz),3.30 (m, 2H), 3.16 (s, 3H), 2.91 (m, 1H), 2.76 (m, 2H), 2.50 (bs, 2H),1.93 (m, 1H), 1.79 (m, 1H), 1.51 (m, 2H). MS (ES) [m+H] calc'd forC₁₈H₂₂N₅O₂, 340.2; found, 340.2.

Further, the toluenesulfonate salt was prepared as follows. A 200 μLaliquot of a 0.03M stock solution of free base was dissolved indichoromethane and concentrated under a slow stream of nitrogen. Theresulting free base was dissolved in 150 μL of solvent (e.g., aceticacid, acetone, ethanol, THF or dicholormethane) and the solution shakenfor 10 minutes. The shaken solution was then charged with 50 μL of a0.126M solution of touenesulfonic acid (1.05 eq.) in dioxane. Thesolution was shaken for 3 hours, followed by removal of the solventsunder a stream of nitrogen to provide the toluenesulfonate salt.

The toluenesulfonate salt was also prepared by dissolving 2 g of thefree base in 10 volumes of acetonitrile and heating the solution to 75°C. for 10 minutes. Then p-toluenesulfonic acid (1.05 equivalents) wasadded and the solution held at 75° C. for 5 minutes. The temperature wasramped down (at about 25° C./hr) and stirred at room temperatureovernight. The product (2.64 g) was dried in a vacuum oven at 50° C. and698.5 mm Hg with a nitrogen sweep for 18 hours.

In each of the above steps, the isolation and/or purification steps ofthe intermediate compounds may be avoided if the intermediates from thereaction mixture are obtained as relatively pure compounds and theby-products or impurities of the reaction mixture do not interfere withthe subsequent reaction steps. Where feasible, one or more isolationsteps may be eliminated to provide shorter processing times, and theelimination of further processing may also afford higher overallreaction yields.

2-{6-[3(R)-Amino-piperidin-1-yl]-3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrileTFA salt (5). The title compound, 5, was prepared from sample 2 usingthe procedures described in the preparation of samples 3 and 4, exceptthat ethyl bromide was used in place of iodomethane. ¹H-NMR (400 MHz,CDCl₃—CD₃OD 10:1): δ 7.66 (d, J=7.8 Hz, 1H), 7.59 (td, J=7.8, 1.4 Hz,1H), 7.40 (t, J=7.6 Hz, 1H), 7.26 (d, J=7.6 Hz, 1H), 5.41 (s, 1H),5.13-5.23 (ABq, 2H, J=41.6, 15.2 Hz), 3.91 (q, J=7.1 Hz, 2H), 3.37 (m,2H), 2.87-2.98 (m, 2H), 2.70 (m, 1H), 2.12 (m, 1H), 1.88 (m, 1H), 1.67(m, 2H), 1.15 (t, J=6.9 Hz, 3H). MS (ES) [m+H] calc'd for C₁₉H₂₄N₅O₂,354.2; found, 354.2.

2-{6-[3(R)-Amino-piperidin-1-yl]-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile(6). The title compound 6 was prepared from compound 2 by the procedureused in preparation of compound 4. ¹H-NMR (400 MHz, CDCl₃—CD₃OD 10:1): δ7.65 (d, J=7.5 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.39 (t, J=7.5 Hz, 1H),7.27 (d, J=7.8 Hz, 1H), 5.32 (s, 1H), 5.13-5.13 (ABq, 2H, J=30.0, 15.0Hz), 3.39 (m, 2H), 2.95 (m, 2H), 2.69 (m, 1H), 2.12 (m, 1H), 1.85 (m,1H), 1.64 (m, 2H). MS (ES) [m+H] calc'd for C₁₇H₂₀N₅O₂, 326.2; found,326.2.

2-{6-[3(R)-Amino-piperidin-1-yl]-5-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile(7). Compound 4 (40 mg, 0.1 mmol) in CHCl₃ (2 mL) was treated with SOCl₂(200 μL) at 100° C. for 30 min, concentrated, and then purified by LC-MSto give the title compound 7. ¹H-NMR (400 MHz, CDCl₃—CD₃OD 10:1): δ 7.73(d, J=7.6 Hz, 1H), 7.64 (t, J=7.6 Hz, 1H), 7.45 (t, J=7.6 Hz, 1H), 7.14(d, J=8.1 Hz, 1H), 5.32-5.42 (m, 2H), 3.43 (s, 3H), 3.33-3.40 (m, 2H),3.17 (m, 2H), 2.87 (s, 1H), 2.08 (m, 1H), 1.70 (m, 1H), 1.32-1.43 (m,2H). MS (ES) [m+H] calc'd for C₁₈H₂₁ClN₅O₂, 374.1; found, 374.1.

6-[3(R)-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-1H-pyrimidine-2,4-dione(8). The title compound was prepared in two steps. The first step wasaccomplished using the procedure for the preparation of compound 2,except that 2-bromobenzylbromide was used in the place ofα-Bromo-o-tolunitrile. The crude product was then converted to the titlecompound by the method used in the preparation of compound 4. ¹H-NMR(400 MHz, CDCl₃—CD₃OD 10:1): δ 7.52 (d, J=8.1 Hz, 1H), 7.24 (t, J=7.8Hz, 1H), 7.10 (t, J=7.8 Hz, 1H), 6.89 (d, J=7.579 Hz, 1H), 5.27 (s, 1H),4.92-5.04 (ABq, J=34.1, 15.0 Hz, 2H), 3.27 (bd, J=10.4 Hz, 1H),3.09-3.18 (m, 1H), 2.89 (m, 1H), 2.70 (t, J=10.9 Hz, 1H), 2.48 (t,J=12.0 Hz, 1H), 2.03 (m, 1H), 1.60-1.71 (m, 1H), 1.42-1.53 (m, 2H). MS(ES) [m+H] calc'd for C₁₆H₂₀BrN₄O₂, 379.1; found, 379.1.

6-[3 (R)-Amino-piperidin-1-yl]-1-(2-iodo-benzyl)-1H-pyrimidine-2,4-dione(9). The title compound was prepared by the procedure described in thepreparation of compound 8, except that 2-iodobenzyl chloride was used asthe benzylating reagent. ¹H-NMR (400 MHz, CDCl₃—CD₃OD 10:1): δ 7.76 (d,J=7.6 Hz, 1H), 7.21 (t, J=7.3 Hz, 1H), 6.89 (t, J=7.2 Hz, 1H), 6.79 (d,J=7.3 Hz, 1H), 5.26 (s, 1H), 4.79-4.92 (ABq, J=34.1, 6.7.0 Hz, 2H), 3.27(m, 1H), 3.13 (s, 1H), 2.85 (d, J=11.6 Hz, 1H), 2.70 (m, 1H), 2.41 (m,1H), 2.02 (m, 1H), 1.60 (m, 1H), 1.45 (m, 2H). MS (ES) [m+H] calc'd forC₁₆H₂₀IN₄O₂, 427.1; found, 427.1.

6-[3(R)-Amino-piperidin-1-yl]-1-(2-bromo-5-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione(10). To a solution of 6-chlorouracil (220 mg, 1.5 mmol) in a mixture ofdry DMF-DMSO (6:1, 5 mL) under nitrogen at 0° C., was added sodiumhydride (60%, 61 mg, 1.8 mmol) in portions. After 0.5 h, lithium bromide(83 mg, 1 mmol) was added and the mixture was stirred for 15 min at 0°C. A solution of 2-bromo-5-fluoro-benzyl bromide (497 mg, 1.8 mmol) inDMF (30 mL) was added dropwise, and stirred at this temperature for 1 h,and then RT overnight. The mixture was evaporated and co-evaporated withwater in vacuo to remove most of the DMF, and then poured intoice-water. The precipitate was collected by filtration, and thensuspended in cold MeOH and filtered. The solution was concentrated togive the crude monobenzylated product.

The crude product was treated with NaH and MeI using the proceduredescribed in the preparation of compound 3, followed by the procedureused in the preparation of compound 4 to give the title compound. ¹H-NMR(400 MHz, CDCl₃—CD₃OD 10:1) δ 7.46 (dd, J=8.7, 5.2 Hz, 1H), 6.82 (td,J=8.3, 2.9 Hz, 1H), 6.59 (dd, J=9.1, 3.0 Hz, 1H), 5.28 (s, 1H),4.99-5.06 (ABq, J=41.7, 16.7 Hz, 2H), 3.28 (m, 1H), 3.23 (s, 3H),3.13-3.21 (m, 1H), 2.86 (bd, J=12.6 Hz, 1H), 2.71 (t, J=10.5 Hz, 1H),2.47 (t, J=11.0 Hz, 1H), 2.00-2.08 (m, 1H), 1.65-1.74 (m, 1H), 1.42-1.53(m, 2H). MS (ES) [m+H] calc'd for C₁₇H₂₁BrFN₄O₂, 411.1; found, 411.1.

6-[3(R)-Amino-piperidin-1-yl]-1-(2-chloro-5-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione(11). The title compound was prepared from compound 1 using the sameprocedures as the preparation of compound 10, except that2-chloro-5-fluoro-benzyl bromide was used in the place of2-bromo-5-fluoro-benzyl bromide. ¹H-NMR (400 MHz, CDCl₃—CD₃OD 10:1): δ7.34-7.40 (dd, J=8.5, 5.1 Hz, 1H), 6.97 (td, J=8.3, 2.9 Hz, 1H), 6.72(dd, J=9.0, 2.9 Hz, 1H), 5.41 (s, 1H), 5.11-5.19 (ABq, J=41.7, 16.7 Hz,2H), 3.37 (s, 1H), 3.32 (s, 3H), 3.23-3.30 (m, 1H), 2.96 (d, J=12.1 Hz,1H), 2.81 (t, J=10.2 Hz, 1H), 2.59 (t, J=11.1 Hz, 1H), 2.13 (d, J=10.4Hz, 1H), 1.76-1.86 (m, 1H), 1.52-1.63 (m, 2H). MS (ES) [m+H] calc'd forC₁₇H₂₁ClFN₄O₂, 367.1; found 367.1.

6-[3(R)-Amino-piperidin-1-yl]-1-(2-chloro-4-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione(12). The title compound was prepared from compound 1 using the sameprocedures as described the preparation of compound 10, except that2-chloro-4-fluoro-benzyl bromide was used in the place of2-bromo-5-fluoro-benzyl bromide. ¹H-NMR (400 MHz, CDCl₃—CD₃OD 10:1) δ7.15 (dd, J=8.211, 2.400 Hz, 1H), 6.95-7.06 (m, 2H), 5.40 (s, 1H),5.09-5.18 (ABq, J=37.7, 15.9 Hz, 2H), 3.33-3.39 (m, 1H), 3.30 (s, 3H),3.23-3.29 (m, 1H), 2.98 (bd, J=12.9 Hz, 1H), 2.79 (t, J=10.4 Hz, 1H),2.55-2.66 (t, J=11.2 Hz, 1H), 2.13 (m, 1H), 1.78-1.88 (m, 1H), 1.55-1.65(m, 2H). MS (ES) [m+H] calc'd for C₁₇H₂₁ClFN₄O₂, 367.1; found 367.1.

6-[3(R)-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-3-methyl-1H-pyrimidine-2,4-dione(13). The title compound was prepared from compound 1 used theprocedures described in the synthesis of compound 10, except that2-bromo benzyl bromide was used in the place of 2-bromo-5-fluoro-benzylbromide. ¹H-NMR (400 MHz, CDCl₃—CD₃OD 10:1): δ 7.45 (d, J=7.8 Hz, 1H),7.16 (t, J=7.5 Hz, 1H), 7.03 (t, J=7.2 Hz, 1H), 6.80 (d, J=7.3 Hz, 1H),5.28 (s, 1H), 4.93-5.05 (ABq, 2H, J=36.4, 16.4 Hz), 3.22 (m, 1H), 3.19(m, 3H), 3.09 (m, 1H), 2.84 (d, J=12.6 Hz, 1H), 2.63 (t, J=10.5 Hz, 1H),2.42 (t, J=10.9 Hz, 1H), 1.97 (d, J=11.1 Hz, 1H), 1.58-1.69 (m, 1H),1.38-1.48 (m, 2H). MS (ES) [m+H] calc'd for C₁₇H₂₂BrN₄O₂, 393.1; found,393.1.

2-{6-[Azepan-3(±)-ylamino]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile(14) and2-{6-[3(±)-Amino-azepan-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile(15). Title compounds 14 and 15 were prepared from compound 3 (70 mg,0.27 mmol) and azepan-3-ylamine (70 mg, 0.61 mg) using the procedure forthe preparation of compound 4. Both compounds were purified by LC-MS.

14: ¹H-NMR (400 MHz, CDCl₃—CD₃OD 10:1) δ 7.77 (d, J=7.8 Hz, 1H), 7.66(t, J=7.6 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 5.54(s, 1H), 5.49 (s, 1H), 5.27-5.36 (ABq, J=26.0, 16.4 Hz, 2H), 3.50 (m,2H), 3.37 (s, 2H), 3.26 (s, 3H), 3.12 (m, 1H), 3.04 (m, 1H), 2.07 (m,1H), 1.86 (m, 1H), 1.60-1.71 (m, 3H). MS (ES) [m+H] calc'd forC₁₉H₂₄N₅O₂, 354.2; found, 354.2.

15: ¹H-NMR (400 MHz, CDCl₃—CD₃OD 10:1) δ 7.77 (d, J=8.1 Hz, 1H), 7.63(t, J=7.6 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 5.48(s, 1H), 5.44-5.52 (ABq, J=61.9, 18.4 Hz, 2H), 3.80 (s, 1H), 3.58-3.50(m, 1H), 3.39-3.39 (m, 1H), 3.26 (s, 3H), 3.13 (m, 1H), 2.89 (t, J=12.4Hz, 1H), 2.04 (m, 1H), 1.93 (m, 1H), 1.86 (m, 2H), 1.59-1.70 (m, 2H). MS(ES) [m+H] calc'd for C₁₉H₂₄N₅O₂, 354.2; found, 354.2.

2-[6-(2-Amino-ethylamino)-3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-benzonitrile(16). Compound 2 (150 mg, 0.57 mmol) in THF-DMSO (6:1, 4 mL) was treatedwith 60% NaH (26 mg, 0.65 mmol), followed by adding ethyl bromide (300uL). In a sealed tube, ˜20% crude product in dry MeOH (3 mL) was treatedNaHCO₃ and ethane-1,2-diamine (200 μL) at 120° C. for 2 h, and purifiedby LC-MS to give the title compound 16. ¹H-NMR (400 MHz, CDCl₃—CD₃OD10:1) δ 7.70 (d, J=7.8 Hz, 1H), 7.58 (t, J=7.7 Hz, 1H), 7.40 (t, J=7.4Hz, 1H), 7.12 (d, J=8.1 Hz, 1H), 5.37 (s, 2H), 3.95 (q, J=6.8 Hz, 2H),3.45 (t, J=5.9 Hz, 2H), 3.11 (t, J=6.1 Hz, 2H), 1.19 (t, J=6.8 Hz, 3H).MS (ES) [m+H] calc'd for C₁₆H₂₀N₅O₂, 314.2; found 314.2.

2-{6-[3(R)-Amino-piperidin-1-yl]-3-(3-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile(17). Compound 2 (65 mg, 0.25 mmol) in DME-DMF (2:1, 2.5 mL) was treatedwith 60% NaH (15 mg, 0.38 mmol) at 0° C. for 20 min, and then LiBr (25mg) was added. 10 min later, m-cyano-benzyl bromide (55 mg, 0.28 mg) wasadded, and the mixture was stirred at RT for 5 h, and concentrated. Thecrude residue was dissolved in MeOH (3 mL). (R)-3-Amino-piperidinedihydrochloride (52 mg, 0.3 mmol) and sodium bicarbonate (100 mg) wereadded. The mixture was heated in a sealed tube at 120° C. for 2 h, andthen filtered and concentrated. LC-MS purification gave the titlecompound 17 in 84% yield. ¹H-NMR (400 MHz, CDCl₃—CD₃OD 10:1) δ 7.67 (d,J=7.8 Hz, 1H), 7.52-7.62 (m, 4H), 7.35-7.46 (m, 2H), 7.27 (d, J=7.8 Hz,1H), 5.43 (s, 1H), 5.15-5.31 (ABq, J=40.9, 13.7 Hz, 2H), 5.04 (s, 2H),3.40 (s, 1H), 3.40 (m 1H), 3.03 (m, 1H), 2.91 (m, 1H), 2.76 (s, 1H),2.13 (s, 1H), 1.92 (m, 1H), 1.63-1.74 (m, 2H). MS (ES) [m+H] calc'd forC₂₅H₂₅N₆O₂, 441.2; found 441.2.

2-{6-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile(18). Title compound 18 was prepared by the methods used in thepreparation of compound 17, except that α-bromo-o-tolunitrile was usedin the place of m-cyano-benzyl bromide. ¹H-NMR (400 MHz, CDCl₃—CD₃OD10:1) δ 7.64 (d, J=6.8 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.8Hz, 2H), 7.44 (t, J=7.6 Hz, 1H), 7.38 (t, J=7.5 Hz, 1H), 7.31 (t, J=7.6Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1H), 5.45 (s, 1H),5.15-5.32 (m, 4H), 3.36-3.47 (m, 2H), 2.98 (m, 2H), 2.10 (m, 1H), 1.91(m, 1H), 1.68 (m, 2H). MS (ES) [m+H] calc'd for C₂₅H₂₅N₆O₂, 441.2; found441.2.

2-{6-[3(R)-Amino-piperidin-1-yl]-3-(4-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile(19). Title compound 19 was prepared by the methods used in thepreparation of compound 17, except that p-cyano-benzyl bromide was usedin the place of m-cyano-benzyl bromide. ¹H-NMR (400 MHz, CDCl₃—CD₃OD10:1) δ 7.70 (d, J=7.8 Hz, 1H), 7.56-7.63 (m, 3H), 7.46 (m, 3H), 7.29(d, J=7.8 Hz, 1H), 5.47 (s, 1H), 5.16-5.36 (ABq, J=51.1, 14.7 Hz, 2H),5.11 (s, 2H), 3.36-3.47 (m, 2H), 2.90-3.07 (m, 2H), 2.79 (s, 1H), 2.15(s, 1H), 1.95 (s, 1H), 1.73 (s, 2H). MS (ES) [m+H] calc'd forC₂₅H₂₅N₆O₂, 441.2; found 441.2.

2-[6-(3-Amino-piperidin-1-yl)-3-(1H-benzoimidazol-2-ylmethyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-benzonitrile(20). Title compound 20 was prepared by the methods used in thepreparation of compound 17, except that 2-chloromethyl benzimidazole wasused in the place of m-cyano-benzyl bromide. ¹H-NMR (400 MHz,CDCl₃—CD₃OD 10:1) δ 7.67 (d, J=3.0 Hz, 1H), 7.65-7.56 (m, 2H), 7.47 (d,J=3.3 Hz, 2H), 7.46 (d, J=3.3 Hz, 1H), 7.37-7.40 (m, 2H), 5.52 (s, 3H),5.23 (s, 2H), 3.51 (d, J=9.6 Hz, 1H), 3.36 (m, 1H), 2.87-2.92 (m, 2H),2.64-2.72 (m, 1H), 2.09 (m, 1H), 1.76 (m, 1H), 1.52-1.64 (m, 2H). MS(ES) [m+H] calc'd for C₂₅H₂₆N₇O₂, 456.2; found 456.2.

2-{6-[3(R)-Amino-piperidin-1-yl]-2,4-dioxo-3-(4-pyrazol-1-yl-benzyl)-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile(21). Title compound 21 was prepared by the methods used in thepreparation of compound 17, except that1-(4-bromomethyl-phenyl)-1H-pyrazole was used in the place ofm-cyano-benzyl bromide. ¹H-NMR (400 MHz, CDCl₃—CD₃OD 10:1) δ 7.90 (d,J=2.5 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.51-7.58(m, 3H), 7.43-7.37 (m, 3H), 7.22 (d, J=7.8 Hz, 1H), 6.47 (t, J=2.1 Hz,1H), 5.43 (s, 1H), 5.14-5.30 (ABq, J=41.2, 16.4 Hz, 2H), 5.05 (s, 2H),3.32-3.40 (m, 2H), 2.96 (m, 1H), 2.89 (m, 1H), 2.70 (m, 1H), 2.10 (m,1H), 1.88 (m, 1H), 1.66 (s, 2H). MS (ES) [m+H] calc'd for C₂₇H₂₈N₇O₂,482.2; found 482.2.

2-{6-[3(R)-Amino-piperidin-1-yl]-2,4-dioxo-3-(3-pyrrol-1-yl-benzyl)-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile(22). Title compound 22 was prepared by the methods used in thepreparation of compound 17, except that1-(3-bromomethyl-phenyl)-1H-pyrrole was used in the place ofm-cyano-benzyl bromide. ¹H-NMR (400 MHz, CDCl₃—CD₃OD 10:1) δ 7.59 (d,J=7.3 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.24-7.36 (m, 4H), 7.21 (t, J=7.6Hz, 2H), 7.02 (t, J=2.1 Hz, 2H), 6.32 (t, J=2.0 Hz, 2H), 5.42 (s, 1H),5.11-5.20 (ABq, J=44.7, 15.9 Hz, 2H), 5.06 (s, 2H), 3.36 (m, 2H), 2.98(m, 1H), 2.89 (m, 1H), 2.70 (m, 1H), 2.10 (m, 1H), 1.88 (m, 1H),1.73-1.58 (m, 2H). MS (ES) [m+H] calc'd for C₂₈H₂₉N₆O₂, 481.2; found481.2.

6-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl]-thiophene-3-carbonitrile(23). Title compound 23 was prepared by the methods used in thepreparation of compound 17, except that2-bromomethyl-thiophene-3-carbonitrile was used in the place ofm-cyano-benzyl bromide. ¹H-NMR (400 MHz, CDCl₃—CD₃OD 10:1) δ 7.65 (d,J=7.6 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.29 (d,J=7.8 Hz, 1H), 7.25 (dd, J=5.3, 1.3 Hz, 1H), 7.11 (dd, J=5.3, 1.0 Hz,1H), 5.45 (s, 1H), 5.35 (s, 2H), 5.15-5.33 (ABq, J=45.0, 15.5 Hz, 2H),3.38 (bd, J=10.1 Hz, 2H), 2.98 (m, 2H), 2.72 (s, 1H), 2.12 (d, J=7.3 Hz,1H), 1.83-1.93 (m, 1H), 1.61-1.72 (m, 2H). MS (ES) [m+H] calc'd forC₂₃H₂₃N₆O₄, 447.1; found 447.1.

3-{4-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl}-benzoicacid methyl ester (24). Title compound 24 was prepared by the methodsused in the preparation of compound 17, except that3-bromomethyl-benzoic acid methyl ester was used in the place ofm-cyano-benzyl bromide. ¹H-NMR (400 MHz, CDCl₃—CD₃OD 10:1) δ 7.99 (s,1H), 7.91 (d, J=7.8 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.56 (d, J=7.9 Hz,1H), 7.52 (d, J=7.6 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.34 (t, J=7.6 Hz,1H), 7.23 (d, J=8.1 Hz, 1H), 5.44 (s, 1H), 5.12-5.31 (ABq, J=43.7, 15.9Hz, 2H), 5.08 (s, 2H), 3.90 (s, 3H), 3.31-3.39 (m, 2H), 2.98 (d, J=11.9Hz, 1H), 2.87 (m, 1H), 2.71 (m, 1H), 2.11 (m, 1H), 1.89 (m, 1H),1.73-1.59 (m, 2H). MS (ES) [m+H] calc'd for C₂₆H₂₈N₅O₄, 474.2; found474.2.

3-{4-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl}-benzoicacid (25). A crude mixture of compound 24 (50 mg) was treated with LiOHin THF-water (10:1) to give the title compound 25. ¹H-NMR (400 MHz,CDCl₃—CD₃OD 10:1) δ 7.90 (s, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.60 (d, J=7.6Hz, 1H), 7.50 (t, J=8.2 Hz, 1H), 7.45 (d, J=7.3 Hz, 1H), 7.26-7.36 (m,2H), 7.17 (d, J=8.1 Hz, 1H), 5.39 (s, 1H), 5.10-5.25 (ABq, J=36.9, 15.5Hz, 2H), 5.03 (s, 2H), 3.31 (m, 2H), 2.95 (m, 1H), 2.81 (m, 1H), 2.64(m, 1H), 2.07 (m, 1H), 1.82 (m, 1H), 1.51-1.68 (m, 2H). MS (ES) [m+H]calc'd for C₂₅H₂₆N₅O₄, 460.2; found 460.2.

6-[3(R)-Amino-piperidin-1-yl]-1,3-bis-(2-bromo-5-fluoro-benzyl)-1H-pyrimidine-2,4-dione(26). The title compound was prepared from 1 by di-benzylation, usingthe procedure for the preparation of 2, except that2-bromo-5-fluoro-benzyl bromide was used in the place ofα-bromo-o-tolunitrile, followed by treatment with 3-(R)-amino-piperidineunder the conditions described in the preparation of compound 4. ¹H-NMR(400 MHz, CDCl₃—CD₃OD 10:1) δ 7.42 (dd, J=8.6, 5.3 Hz, 2H), 7.11-7.08(dd, J=9.1, 2.2 Hz, 1H), 7.06 (dd, J=9.3, 2.8 Hz, 1H), 6.78-6.84 (m,2H), 5.71 (s, 1H), 5.29 (s, 4H), 4.22 (d, J=11.1 Hz, 1H), 3.82 (d,J=13.4 Hz, 1H), 3.07-3.24 (m, 3H), 2.06 (m, 1H), 1.75-1.83 (m, 1H),1.63-1.72 (m, 1H), 1.50-1.59 (m, 1H). MS (ES) [m+H] calc'd forC₂₃H₂₃Br₂F₂N₃O₂, 583.01; found 583.01.

2-{6-[3(R)-Amino-piperidin-1-yl]-5-chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile(27). Compound 4 (100 mg) in THF (2 mL) was treated with 4M HCl indioxane (1 mL) at rt for 1 h, concentrated, and then purified by LC-MSto give the title compound. ¹H-NMR (400 MHz, DMSO-D6): 6 ppm 12.0 (s,1H), 7.88 (d, J=7.6 Hz, 1H), 7.68 (t, J=7.7 Hz, 1H), 7.49 (t, J=7.7 Hz,1H), 7.36 (d, J=7.8 Hz, 1H), 5.09-5.21 (m, 2H), 3.17 (m, 2H), 2.96 (t,J=11.1 Hz, 1H), 2.86 (d, J=10.6 Hz, 1H), 2.65 (m, 1H), 1.90 (d, J=11.6Hz, 1H), 1.57 (d, J=13.1 Hz, 1H), 1.19-1.31 (m, 1H), 1.03-1.15 (m, 1H).MS (ES) [m+H] calc'd for C₁₇H₁₉ClN₅O₂, 360.1; found, 360.1.

6-[3(R)-Amino-piperidin-1-yl]-1-(2,5-di-chloro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione(28). The title compound was prepared from compound 1 using the sameprocedures as in the preparation of compound 10, except that2,5-di-chloro-benzyl bromide was used in the place of2-bromo-5-fluoro-benzyl bromide. ¹H-NMR (400 MHz, CDCl₃—CD₃OD 10:1): 6ppm 7.50 (d, J=8.6 Hz, 1H), 7.39 (dd, J=8.3, 2.526 Hz, 1H), 7.22 (d,J=2.5 Hz, 1H), 5.41 (s, 1H), 5.01-4.93 (ABq, J=41.9, 16.2 Hz, 2H), 3.25(m, 2H), 3.10 (s, 3H), 2.85 (m, 1H), 2.76 (m, 1H), 2.67 (m, 1H), 1.91(m, 1H), 1.75 (m, 1H), 1.45 (m, 2H). MS (ES) [m+H] calc'd forC₁₇H₂₁Cl₂N₄O₂, 383.1; found 383.1.

6-[3(R)-Amino-piperidin-1-yl]-1-(2-chloro-3,6-di-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione(29). The title compound was prepared from compound 1 using the sameprocedures as in the preparation of compound 10, except that2-chloro-3,6-di-fluoro-benzyl bromide was used in the place of2-bromo-5-fluoro-benzyl bromide. ¹H NMR (400 MHz, CDCl₃—CD₃OD 10:1) δppm 6.98-7.06 (m, 2H), 6.90 (m, 2H), 5.31 (s, 1H), 5.01-5.20 (ABq,J=24.2, 14.4 Hz, 2H), 3.28-3.37 (m, 2H) 3.13 (s, 3H), 3.01-2.94 (m, 1H),2.6-2.9 (m, 2H), 2.10 (m, 1H), 1.92 (m, 2H), 1.73 (s, 1H), 1.6-1.75 (m,2H). MS (ES) [m+H] calc'd for C₁₇H₂₀ClF₂N₄O₂, 385.1; found 385.1.

(R)-2-((6-(3-amino-3-methylpiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrile(30).2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile(300 mg, 1.0 mmol), (R)-3-amino-3-methyl-piperidine dihydrochloride (266mg, 1.4 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were stirred ina sealed tube in EtOH (3 mL) at 100° C. for 2 hrs. The final compoundwas obtained as TFA salt after HPLC purification. ¹H-NMR (400 MHz,CD₃OD): δ. 7.78-7.83 (m, 1H), 7.14-7.26 (m, 2H), 5.47 (s, 1H), 5.12-5.36(ABq, 2H, J=105.2, 15.6 Hz), 3.21 (s, 1H), 2.72-3.15 (m, 4H), 1.75-1.95(m, 4H), 1.39 (s, 3H). MS (ES) [m+H] calc'd for C19H22FN5O2, 372.41;found, 372.41.

4-Fluoro-2-methylbenzonitrile (31). A mixture of 2-bromo-5fluorotoluene(3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was refluxedfor 24 hours. The reaction was diluted with water and extracted withhexane. The organics were dried over MgSO₄ and the solvent removed togive product 31 (yield 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.60 (dd, J=5.6,8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).

2-Bromomethyl-4-fluorobenzonitrile (32). A mixture of4-fluoro-2-methylbenzonitrile (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol)and AIBN (100 mg) in CCl₄ was refluxed under nitrogen for 2 hours. Thereaction was cooled to room temperature. The solid was removed byfiltration. The organic solution was concentrated to give crude productas an oil, which was used in the next step without further purification.¹H-NMR (400 MHz, CDCl₃): δ 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd,J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).

2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile(33). A mixture of crude 3-methyl-6-chlorouracil (0.6 g, 3.8 mmol),2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K₂CO₃ (0.5 g, 4mmol) in DMSO (10 mL) was stirred at 60° C. for 2 hours. The reactionwas diluted with water and extracted with EtOAc. The organics were driedover MgSO₄ and the solvent removed. The residue was purified by columnchromatography. 0.66 g of the product was obtained (yield: 60%). ¹H-NMR(400 MHz, CDCl₃): δ 7.73 (dd, J=7.2, 8.4 Hz, 1H), 7.26 (d, J=4.0 Hz,1H), 7.11-7.17 (m, 1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H),3.39 (s, 3H). MS (ES) [m+H] calc'd for C₁₃H₉ClFN₃O₂, 293.68; found293.68.

2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile(34).2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile(300 mg, 1.0 mmol), (R)-3-amino-piperidine dihydrochloride (266 mg, 1.5mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a sealedtube in EtOH (3 mL) at 100° C. for 2 hrs. The final compound wasobtained as TFA salt after HPLC purification. ¹H-NMR (400 MHz, CD₃OD):δ. 7.77-7.84 (m, 1H), 7.16-7.27 (m, 2H), 5.46 (s, 1H), 5.17-5.34 (ABq,2H, J=35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m,1H), 2.67-2.92 (m, 2H), 2.07-2.17 (m, 1H), 1.82-1.92 (m, 1H), 1.51-1.79(m, 2H). MS (ES) [m+H] calc'd for C₁₈H₂₀FN₅O₂, 357.38; found, 357.38.

The TFA salt (34) was suspended in DCM, and then washed with saturatedNa₂CO₃. The organic layer was dried and removed in vacuo. The residuewas dissolved in acetonitrile and HCl in dioxane (1.5 eq.) was added at0° C. The HCl salt was obtained after removing the solvent. ¹H-NMR (400MHz, CD₃OD): δ. 7.77-7.84 (m, 1H), 7.12-7.26 (m, 2H), 5.47 (s, 1H),5.21-5.32 (ABq, 2H, J=32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H),3.01-3.1 (m, 1H), 2.69-2.93 (m, 2H), 2.07-2.17 (m, 1H), 1.83-1.93 (m,1H), 1.55-1.80 (m, 2H). MS (ES) [m+H] calc'd for C₁₈H₂₀FN₅O₂, 357.38;found, 357.38.

The product was also converted to a variety of corresponding acidaddition salts. Specifically, the benzonitrile product (approximately 10mg) in a solution of MeOH (1 mL) was treated with various acids (1.05equivalents). The solutions were allowed to stand for three days open tothe air. If a precipitate formed, the mixture was filtered and the saltdried. If no solid formed, the mixture was concentrated in vacuo and theresidue isolated. In this way, salts of 34 were prepared from thefollowing acids: benzoic, p-toluenesulfonic, succinic, R-(−)-Mandelicand benzenesulfonic. The succinate was found to be crystalline asdetermined by x-ray powder diffraction analysis.

In addition, the methanesulfonate salt was prepared as follows. A 10.5 galiquot of the benzonitrile product was mixed with 400 mL ofisopropylacetate. The slurry was heated to 75° C. and filtered through#3 Whatman filter paper. The solution was heated back to 75° C. and a 1Msolution of methanesulfonic acid (30.84 mL) was added slowly over 10minutes while stirring. The suspension was cooled to room temperature ata rate of about 20° C./hr. After 1 hr at room temperature, the solid wasfiltered and dried in an oven overnight to obtain the methanesulfonatesalt.

Examples of In Vitro Assays

The protease inhibitory activities of DPP-IV inhibitors can be readilydetermined by methods known to those of ordinary skill in the art sincesuitable in vitro assays for measuring protease activity and theinhibition thereof by test compounds are known. Examples of assays thatmay be used for measuring protease inhibitory activity and selectivityare set forth below.

DPP-IV Assay

Solutions of test compounds in varying concentrations (≦10 mM finalconcentration) were prepared in Dimethyl Sulfoxide (DMSO) and thendiluted into assay buffer comprising: 20 mM Tris, pH 7.4; 20 mM KCl; and0.1 mg/mL BSA. Human DPP-IV (0.1 nM final concentration) was added tothe dilutions and pre-incubated for 10 minutes at ambient temperaturebefore the reaction was initiated withA-P-7-amido-4-trifluoromethylcoumarin (AP-AFC; 10 μM finalconcentration). The total volume of the reaction mixture was 10-100 μLdepending on assay formats used (384 or 96 well plates). The reactionwas followed kinetically (excitation λ=400 nm; emission λ=505 nm) for5-10 minutes or an end-point was measured after 10 minutes. Inhibitionconstants (IC₅₀) were calculated from the enzyme progress curves usingstandard mathematical models.

FAPα Assay

Solutions of test compounds in varying concentrations (≦10 mM finalconcentration) were prepared in Dimethyl Sulfoxide (DMSO) and thendiluted into assay buffer comprising: 20 mM Tris, pH 7.4; 20 mM KCl; and0.1 mg/mL BSA. Human FAPα (2 nM final concentration) was added to thedilutions and pre-incubated for 10 minutes at ambient temperature beforethe reaction was initiated with A-P-7-amido-4-trifluoromethylcoumarin(AP-AFC; 40 μM final concentration). The total volume of the reactionmixture was 10-100 μL depending on assay formats used (384 or 96 wellplates). The reaction was followed kinetically (excitation λ=400 nm;emission λ=505 nm) for 5-10 minutes or an end-point was measured after10 minutes. Inhibition constants (IC₅₀) were calculated from the enzymeprogress curves using standard mathematical models.

PREP Assay

Solutions of test compounds in varying concentrations (≦10 mM finalconcentration) were prepared in Dimethyl Sulfoxide (DMSO) and thendiluted into assay buffer comprising: 20 mM Sodium Phosphate, pH 7.4;0.5 mM EDTA; 0.5 mM DTT; and 0.1 mg/mL BSA. PREP (EC3.4.21.26 fromFlavobacterium meningosepticum; 0.2 nM final concentration) was added tothe dilutions. The PREP and compound were pre-incubated for 10 minutesat ambient temperature before the reaction was initiated with Z-G-P-AMC(10 μM final concentration). The total volume of the reaction mixturewas 10-100 μL depending on assay formats used (384 or 96 well plates).The reaction was followed kinetically (excitation λ=375 nm; emissionλ=460 nm) for 10 minutes or an end-point was measured after 10 minutes.Inhibition constants (IC₅₀) were calculated from the enzyme progresscurves using standard mathematical models.

Tryptase Assay

Solutions of test compounds in varying concentrations (≦10 mM finalconcentration) were prepared in Dimethyl Sulfoxide (DMSO) and thendiluted into assay buffer comprising: 100 mM Hepes, pH 7.4; 0.01%Brij35; and 10% glycerol. Tryptase (rhLung beta; 0.1 nM finalconcentration) was added to the dilutions and pre-incubated withcompound for 10 minutes at ambient temperature. The enzymatic reactionwas initiated with 25 μM Z-lys-SBzl and 400 μM DTNB. The total volume ofthe reaction mixture was 100 μL in Costar A/2 96 well plates. Thereaction was followed calorimetrically (λ=405 nm) for 10 minutes.Inhibition constants (IC₅₀) were calculated from the enzyme progresscurves using standard mathematical models.

Compounds of the invention were tested according to the above-describedassays for protease inhibition and observed to exhibit selective DPP-IVinhibitory activity. For example, compounds of the invention were foundto inhibit DPP-IV activity at concentrations that are at least 50 foldless than those concentrations required to produce an equiactiveinhibition of protease activity for FAPα. The apparent inhibitionconstants (K_(i)) for compounds of the invention, against DPP-IV, werein the range from about 10⁻⁹M to about 10⁻⁵M.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to the compounds, compositions,kits, and methods of the present invention without departing from thespirit or scope of the invention. Thus, it is intended that the presentinvention cover the modifications and variations of this inventionprovided they come within the scope of the appended claims and theirequivalents.

1. A compound of the formula

or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof.
 2. The compound according to claim1, wherein the compound is present as a mixture of stereoisomers.
 3. Thecompound according to claim 1, wherein the compound comprises a singlestereoisomer.
 4. A compound of the formula

or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof.
 5. A compound of the formula

wherein the compound is present as a succinate salt, or a polymorph,solvate, ester, tautomer or enantiomer thereof.
 6. The compoundaccording to claim 5, wherein the compound is present as a mixture ofstereoisomers.
 7. The compound according to claim 6, wherein thecompound is present as a single stereoisomer.
 8. A compound of theformula

wherein the compound is present as a succinate salt, or a polymorph,solvate, ester, tautomer or enantiomer thereof.
 9. A pharmaceuticalcomposition comprising, as an active ingredient, a compound of theformula

or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof.
 10. The pharmaceutical compositionaccording to claim 9, wherein the composition is a solid formulationadapted for oral administration.
 11. The pharmaceutical compositionaccording to claim 9, wherein the composition is a tablet.
 12. Thepharmaceutical composition according to claim 9, wherein the compositionis a liquid formulation adapted for oral administration.
 13. Thepharmaceutical composition according to claim 9, wherein the compositionis a liquid formulation adapted for parenteral administration.
 14. Thepharmaceutical composition according to claim 9, wherein the compositionis adapted for administration by a route selected from the groupconsisting of orally, parenterally, intraperitoneally, intravenously,intraarterially, transdermally, sublingually, intramuscularly, rectally,transbuccally, intranasally, liposomally, via inhalation, vaginally,intraoccularly, via local delivery, subcutaneously, intraadiposally,intraarticularly, and intrathecally.
 15. A pharmaceutical compositioncomprising, as an active ingredient, a compound of the formula

wherein the compound is present as a succinate salt, or a polymorph,solvate, ester, tautomer or enantiomer thereof.
 16. The pharmaceuticalcomposition according to claim 15, wherein the composition is a solidformulation adapted for oral administration.
 17. The pharmaceuticalcomposition according to claim 15, wherein the composition is a tablet.18. The pharmaceutical composition according to claim 15, wherein thecomposition is a liquid formulation adapted for oral administration. 19.The pharmaceutical composition according to claim 15, wherein thecomposition is a liquid formulation adapted for parenteraladministration.
 20. The pharmaceutical composition according to claim15, wherein the composition is adapted for administration by a routeselected from the group consisting of orally, parenterally,intraperitoneally, intravenously, intraarterially, transdermally,sublingually, intramuscularly, rectally, transbuccally, intranasally,liposomally, via inhalation, vaginally, intraoccularly, via localdelivery, subcutaneously, intraadiposally, intraarticularly, andintrathecally.
 21. A kit comprising: a compound of the formula

 or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, and instructions which comprise oneor more forms of information selected from the group consisting ofindicating a disease state for which the compound is to be administered,storage information for the compound, dosing information andinstructions regarding how to administer the compound.
 22. The kitaccording to claim 21, wherein the kit comprises the compound in amultiple dose form.
 23. A kit comprising: a compound of the formula

 wherein the compound is present as a succinate salt, or a polymorph,solvate, ester, tautomer or enantiomer thereof; and instructions whichcomprise one or more forms of information selected from the groupconsisting of indicating a disease state for which the compound is to beadministered, storage information for the compound, dosing informationand instructions regarding how to administer the compound.
 24. The kitaccording to claim 23, wherein the kit comprises the compound in amultiple dose form.
 25. An article of manufacture comprising: a compoundof the formula

 or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof; and packaging materials.
 26. Thearticle of manufacture of claim 25, wherein the packaging materialcomprises a container for housing the compound.
 27. The article ofmanufacture of claim 26, wherein the container comprises a labelindicating one or more members of the group consisting of a diseasestate for which the compound is to be administered, storage information,dosing information and/or instructions regarding how to administer thecomposition.
 28. The article of manufacture of claim 25, wherein thearticle of manufacture comprises the compound in a multiple dose form.29. An article of manufacture comprising: a compound of the formula

 wherein the compound is present as a succinate salt, or a polymorph,solvate, ester, tautomer or enantiomer thereof; and packaging materials.30. The article of manufacture of claim 29, wherein the packagingmaterial comprises a container for housing the compound.
 31. The articleof manufacture of claim 30, wherein the container comprises a labelindicating one or more members of the group consisting of a diseasestate for which the compound is to be administered, storage information,dosing information and/or instructions regarding how to administer thecomposition.
 32. The article of manufacture of claim 29, wherein thearticle of manufacture comprises the compound in a multiple dose form.33. A method of inhibiting DPP-IV comprising: contacting DPP-IV with acompound of the formula

or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof.
 34. A method of inhibiting DPP-IVcomprising: causing a compound of the formula

or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, to be present in a subject in orderto inhibit DPP-IV in vivo.
 35. A method of inhibiting DPP-IV comprising:administering a first compound to a subject that is converted in vivo toa second compound wherein the second compound inhibits DPP-IV in vivo,the second compound being a compound of the formula

or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof.
 36. A therapeutic method comprising:administering a compound of the formula

or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, to a subject.
 37. A method oftreating a disease state for which DPP-IV possesses activity thatcontributes to the pathology and/or symptomology of the disease state,the method comprising causing a compound of the formula

or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, to be present in a subject in atherapeutically effective amount for the disease state.
 38. A method oftreating diabetes in a patient in need thereof, comprising administeringto said patient a therapeutically effective amount of a compound of theformula

or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof.
 39. The method according to claim38, wherein the disease is type I or type II diabetes.
 40. A method oftreating cancer in a patient in need thereof, comprising administeringto said patient a therapeutically effective amount of a compoundaccording to claim
 1. 41. The method of claim 40, wherein the cancertreated is colorectal, prostate, breast, thyroid, skin, lung, or headand neck.
 42. A method of treating an autoimmune disorder in a patientin need thereof, comprising administering to said patient atherapeutically effective amount of a compound according to claim
 1. 43.The method of claim 42, wherein the autoimmune disorder is selected fromthe group consisting of rheumatoid arthritis, psoriasis, and multiplesclerosis.
 44. A method of treating a condition characterized byinadequate lymphocyte or hemapoietic cell activation or concentration ina patient in need thereof, comprising administering to said patient atherapeutically effective amount of a compound according to claim
 1. 45.The method of claim 44, wherein said condition is a side effect ofchemotherapy or radiation therapy.
 46. The method of claim 44, whereinsaid condition is a result of kidney failure.
 47. The method of claim44, wherein said condition is a result of a bone marrow disorder.
 48. Amethod of treating HIV infection in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a compound according to claim
 1. 49. A method of treating acondition characterized by immunodeficiency symptoms in a patient inneed thereof, comprising administering to said patient a therapeuticallyeffective amount of a compound according to claim
 1. 50. A method ofinhibiting DPP-IV comprising: contacting DPP-IV with a compoundaccording to claim
 8. 51. A method of inhibiting DPP-IV comprising:causing a compound according to claim 8 to be present in a subject inorder to inhibit DPP-IV in vivo.
 52. A method of inhibiting DPP-IVcomprising: administering a first compound to a subject that isconverted in vivo to a second compound wherein the second compoundinhibits DPP-IV in vivo, the second compound being a compound accordingto claim
 8. 53. A therapeutic method comprising: administering acompound according to claim 8 to a subject.
 54. A method of treating adisease state for which DPP-IV possesses activity that contributes tothe pathology and/or symptomology of the disease state, the methodcomprising causing a compound according to claim 8 to be present in asubject in a therapeutically effective amount for the disease state. 55.A method of treating diabetes in a patient in need thereof, comprisingadministering to said patient a therapeutically effective amount of acompound according to claim
 8. 56. The method according to claim 55,wherein the disease is type I or type II diabetes.
 57. A method oftreating cancer in a patient in need thereof, comprising administeringto said patient a therapeutically effective amount of a compoundaccording to claim
 8. 58. The method of claim 57, wherein the cancertreated is colorectal, prostate, breast, thyroid, skin, lung, or headand neck.
 59. A method of treating an autoimmune disorder in a patientin need thereof, comprising administering to said patient atherapeutically effective amount of a compound according to claim
 8. 60.The method of claim 59, wherein the autoimmune disorder is selected fromthe group consisting of rheumatoid arthritis, psoriasis, and multiplesclerosis.
 61. A method of treating a condition characterized byinadequate lymphocyte or hemapoietic cell activation or concentration ina patient in need thereof, comprising administering to said patient atherapeutically effective amount of a compound according to claim
 8. 62.The method of claim 61, wherein said condition is a side effect ofchemotherapy or radiation therapy.
 63. The method of claim 61, whereinsaid condition is a result of kidney failure.
 64. The method of claim61, wherein said condition is a result of a bone marrow disorder.
 65. Amethod of treating HIV infection in a patient in need thereof,comprising administering to said patient a therapeutically effectiveamount of a compound according to claim
 8. 66. A method of treating acondition characterized by immunodeficiency symptoms in a patient inneed thereof, comprising administering to said patient a therapeuticallyeffective amount of a compound according to claim
 8. 67. A process forproducing a product of the formula

the process comprising the steps of: (i) contacting a compound of theformula A

wherein Hal is halogen; with a compound of the formula B

wherein LG is a leaving group; under conditions sufficient to produce acompound of the formula C

(ii) contacting the compound of formula C with a compound of formula DH₃C-LG′  D wherein LG′ is a leaving group; under conditions sufficientto produce a compound of the formula E;

(iii) contacting the compound of formula E with a compound of formula

under conditions sufficient to produce the product.
 68. The process ofclaim 67, wherein Hal is selected from the group consisting of Br, Cland F.
 69. The process of claim 67, wherein the leaving group LG′ isselected from the group consisting of Br, Cl and I.
 70. The process ofclaim 67, wherein step (ii) further comprises the addition of a base.71. The process of claim 70, wherein the base is potassium carbonate.72. The process of claim 67, wherein product E is further purifiedbefore being subjected to step (iii).
 73. The process of claim 72,wherein the purification of product E is performed by solvent washesand/or by chromatography.
 74. The process of claim 67, wherein step iii)further comprises a purification step of washing of the product withorganic solvents or mixture of solvents and/or by column chromatography.75. The process of claim 67, further comprising the step of reacting theproduct with an acid to produce an acid addition salt.
 76. The processof claim 75, wherein the acid addition salt is a hydrochloric acid salt.77. The process of claim 75, wherein the acid addition salt is asuccinate salt.
 78. The process of claim 75, wherein the acid additionsalt is a methanesulfonate salt.
 79. The process of claim 67, whereinthe product is present in a mixture of stereoisomers.
 80. The process ofclaim 67, wherein the product is present as a single stereoisomer.
 81. Aprocess for producing a product of the formula

the process comprising the steps of (i) admixing6-chloro-1H-pyrimidine-2,4-dione with an aryl halide of the formula

wherein Hal is Br, Cl, or I, under condition sufficient to produce acompound of the formula

(ii) alkylating the above product with a methyl halide under conditionssufficient to form a compound of the formula

(iii) condensing the above product with a compound of the formula


82. The process of claim 81, further comprising the step of reacting theproduct with an acid to produce an acid addition salt.
 83. The processof claim 82, wherein the acid addition salt is a hydrochloric acid salt.84. The process of claim 82, wherein the acid addition salt is asuccinate salt.
 85. The process of claim 82, wherein the acid additionsalt is a methanesulfonate salt.